Pyridazinone derivatives with pharmaceutical activity

ABSTRACT

A 3(2H)-pyridazinone derivative of the formula (I) its salt, a process for its production and a pharmaceutical composition containing it. ##STR1## wherein each of R 1 , R 2  and R 3  which are independent of one another, is a hydrogen atom or a C 1-4  alkyl group, X is a chlorine atom or a bromine atom, Y 1  is a hydrogen atom, a halogen atom, a nitro group, an amino group or a C 1-4  alkoxy group, Y 2  is a hydrogen atom, a halogen atom, a hydroxyl group, a C 1-4  alkyl group or a C 1-4  alkoxy group, A is a C 1-5  alkylene chain which may be substituted by a hydroxyl group, B is a carbonyl group or a methylene chain which may be substituted by a C 1-4  alkyl group, and each of R 4  and R 5  which are independent of each other, is a C 1-4  alkyl group, or R 4  is a hydrogen atom and R 5  is --Z--Ar (wherein Z is a C 1-5  alkylene chain, and Ar is an aromatic 6-membered ring which may contain a nitrogen atom), or R 4  and R 5  together form a C 2-6  cyclic alkylene group, or R 4  and R 5  form together with the adjacent nitrogen atom a 4-substituted piperazine ring of the formula: ##STR2## wherein R 6  is a C 1-4  alkyl group.

TECHNICAL FIELD

The present invention relates to novel 3(2H)-pyridazinone derivativesand their pharmaceutically acceptable salts having bronchodilatoractivities, antiallergy activities and/or antiplatelet activities.

BACKGROUND ART

1) Field of bronchodilator

In the treatment of chronic reversible obstructive respiratory diseasessuch as bronchial asthma, bronchitis and adult respiratory distresssyndrome, air way remission at the time of seizure is important. Forsuch a purpose, bronchodilators are used. Major bronchodilatorspresently used for clinical purposes may be generally classified intoβ-stimulants including Salbutamol and xanthine drugs represented bytheophylline. The former drugs have a drawback that the effects decreaseagainst intractable diseases, and a deterioration of the sympton due tofrequent long-term administration has been pointed out in the treatmentof bronchial asthma (The New England Journal of Medicine, vol 321, p.1517-1527, 1989).

On the other hand, theophylline drugs have a limited use since theirsafety range is narrow.

2) Field of antiallergic drug

Various in vivo chemical mediators are believed to take part inimmediate allergy diseases such as bronchial asthma, allergic rhinitis,hives and hey fever. Among them, histamine is one of importantmediators, and antihistamic agents have been used as antiallergic drugssince long ago. However, many of antiallergic drugs of antihistamic typehave central side effects such as drowsiness. For the treatment ofasthma, a drug which has not only an antiallergic activity but also abronchodilator activity will be significant from the viewpoint of thetreatment and economy, but a drug having such functions has not yet beenclinically developed.

3) Field of antiplatelet agent

It is known that platelets play an important role for thrombus formationin connection with a disease state through activation by stimulation,adhesion to vascular walls and aggregation. Various thrombotic diseasescaused by thrombus formation include, for example, cerebral thrombosis,pulmonal thrombosis, myocardial infarction, angina pectoris andocclusion of peripheral artery, as main diseases, and all of thesediseases require development of useful drugs. As a prophylactic ortherapeutic drug, an attention has been drawn to an antiplatelet agenthaving an inhibitory activity of platelet aggregation. Heretofore, theeffect of aspirin has been widely studied, and more recently ticlopidineand cilostazol have been clinically developed. However, a more stronglyeffective drug is desired in respect of its effects.

In addition to the above-mentioned various thrombotic diseases, thereare enumerated various diseases in relation to platelets. Examples ofthese diseases include nephritis, cancer cell metastasis and the like,and recently various studies have been conducted with regard toprophylactic or therapeutic effects for these diseases achieved mainlyby an anti-thrombotic agent having an activity for controlling plateletfunction ("Journal of Royal College of Physicians", Vol. 7, No. 1, p.5-18, 1972; "Japan Clinics (Nihon Rinsho)", Vol. 4, No. 6, p. 130-136,1988; Anticancer Research, Vol 6, p. 543-548, 1986).

Now, the relationship of 5-ω-aminoalkyleneoxy orω-aminocarbonylalkyeneoxy substituted benzylamino)-3(2H)-pyridazinonederivatives of the formula (I) and their pharmaceutically acceptablesalts according to the present invention with the compounds disclosed inpublished references will be described.

Compounds of the type wherein a substituted benzylamino group is bondedto the 5-position of a 3(2H)-pyridazinone ring, which are relativelysimilar to the compounds of the present invention, are disclosed in thefollowing references.

(a) Japanese Patent Publication No. 41455/1994, EP186817B or U.S. Pat.No. 5,098,900 (hereinafter referred to as reference (a)) disclosescompounds including 3(2H)-pyridazinone derivatives wherein the2-position is a lower alkyl group, the 4-position is a chlorine atom ora bromine atom, the 5-position is a benzylamino group having the benzenering substituted by a substituent including a ω-aminoalkyl group, aω-carbamoylalkyleneoxy group, a ω-N-mono loweralkylaminocarbonylalkyleneoxy group and an aminocarbonyl group, andtheir pharmaceutical use as anti SRS-A agents and their pharmacologicalactivities.

(b) Japanese Unexamined Patent Publication No. 030769/1987, EP201765B orU.S. Pat. No. 4,892,947 (hereinafter referred to as reference (b))discloses compounds including 3(2H)-pyridazinone derivatives wherein the2-position is a hydrogen atom, the 4-position is a chlorine atom or abromine atom, the 5-position is a benzylamino group having the benzenering substituted by a substituent including an alkyloxy group, aω-phenylalkyleneoxy group and a dialkylamino group, and the 6-positionis a hydrogen atom, and their pharmaceutical use as anti SRS-A agentsand their pharmacological activities.

(c) Japanese Unexamined Patent Publication No. 301870/1988, EP275997B orU.S. Pat. No. 4,978,665 (hereinafter referred to as reference (c))discloses compounds including 3(2H)-pyridazinone derivatives wherein the2-position is a hydrogen atom or a lower alkyl group, the 4-position isa chlorine atom or a bromine atom, the 5-position is a benzylamino grouphaving the benzene ring substituted by a substituent including analkyloxy group, a ω-phenylalkyleneoxy group and a dialkylamino group,and the 6-position is a halogen atom, a nitro group, an amino group oran alkoxy group, and their pharmaceutical use as anti SRS-A agents andtheir pharmacological activities.

(d) W091/16314, EP482208A or U.S. Pat. No. 5,202,323 (hereinafterreferred to as reference (d)) discloses compounds including3(2H)-pyridazinone derivatives wherein the 2-position is a hydrogen atomor a lower alkyl group, the 4-position is a chlorine atom or a bromineatom, the 5-position is a benzylamino group having the benzene ringsubstituted by a substituent including an alkyloxy group, aω-phenylalkyleneoxy group wherein the benzene ring may be substituted byan alkyl group or a halogen atom, a ω-alkoxycarbonylalkyleneoxy groupand a ω-aminocarbonylalkyleneoxy group, and the 6-position is analkyleneoxy group having a various functional group at the ω-position,and their pharmaceutical uses as antithrombotic agents, cardiotonicagents, vasodilators and anti SRS-A agents and their pharmacologicalactivities.

DISCLOSURE OF THE INVENTION

As a result of an extensive study, the present inventors have discoveredthat the 3(2H)-pyridazinone derivatives and their pharmaceuticallyacceptable salts of the present invention, which are different from anyof the compounds disclosed in the above references (a) to

(d), are superior compounds for vasodilators, antiallergic drugs or/andantiplatelet agents, they show particularly excellent activities by oraladministration, and they are useful as active ingredients ofprophylactic or therapeutic drugs for e.g. the above-mentionedrespiratory diseases, immediate allergic diseases or/and thromboticdiseases. The present invention has been accomplished on the basis ofthis discovery.

That is, the present invention provides a 3(2H)-pyridazinone derivativeof the formula (I) and its pharmaceutically acceptable salt, a processfor producing the same and a pharmaceutical composition containing thesame as an active ingredient: ##STR3## wherein each of R¹, R² and R³which are independent of one another, is a hydrogen atom or a C₁₋₄ alkylgroup, X is a chlorine atom or a bromine atom, Y¹ is a hydrogen atom, ahalogen atom, a nitro group, an amino group or a C₁₋₄ alkoxy group, Y²is a hydrogen atom, a halogen atom, a hydroxyl group, a C₁₋₄ alkyl groupor a C₁₋₄ alkoxy group, A is a C₁₋₅ alkylene chain which may besubstituted by a hydroxyl group, B is a carbonyl group or a methylenechain which may be substituted by a C₁₋₄ alkyl group, and each of R⁴ andR⁵ which are independent of each other, is a C₁₋₄ alkyl group, or R⁴ isa hydrogen atom and R⁵ is --Z--Ar (wherein Z is a C₁₋₅ alkylene chain,and Ar is an aromatic 6-membered ring which may contain one or twonitrogen atoms), or R⁴ and R⁵ together form a C₂₋₆ cyclic alkylenegroup, or R⁴ and R⁵ form together with the adjacent nitrogen atom a4-substituted piperazine ring of the formula: ##STR4## {wherein R⁶ is aC₁₋₄ alkyl group (this alkyl group may be substituted by one or moresubstituents selected from a group of substituents consisting of a C₁₋₄alkyl group, a phenyl group which may be substituted by Y³ (wherein Y³is a hydrogen atom, a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxygroup, an amino group, an N-formyl group or a C₁₋₄ alkylcarbonylaminogroup), ##STR5## (wherein each of R⁷ and R⁸ is a hydrogen atom, or R⁷and R⁸ form together with the carbon atoms to which they are bonded, abenzene ring, and each of A, B, C and D which are independent of oneanother, is a nitrogen atom or a carbon atom) and ##STR6## (wherein Y³is as defined above, and R⁹ is a C₁₋₄ alkyl group or a benzyl groupwhich may be substituted by a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group or ahalogen atom)) or --COR¹⁰ (wherein R¹⁰ is a hydrogen atom or a C₁₋₄alkyl group)} or a 4-substituted piperidine ring of the formula:##STR7## {wherein R¹¹ is a C₁₋₄ alkyl group (this alkyl group may besubstituted by one or more substituents selected from a group ofsubstituents consisting of a phenyl group which may be substituted by Y³(wherein Y³ is as defined above) and a hydroxyl group)}.

Now, R¹, R², R³, R⁴, R⁵, A, B, X, Y¹ and Y² in the compound of theformula (I) of the present invention will be described.

Specific examples of each of R¹, R² and R³ include a hydrogen atom, amethyl group, an ethyl group, a n-propyl group, an i-propyl group, an-butyl group, an i-butyl group, a sec-butyl group and a t-butyl group.A hydrogen atom is preferred for each of them.

A is an alkylene chain having a total carbon number of from 1 to 5 whichmay be substituted by a hydroxyl group or an alkyl group at any optionalposition and may, for example, be a bond species such as a methylenegroup, an ethylene group, a propylene group, a butylene group or apentylene group. More preferred is a linear alkylene group having from 1to 4 carbon atoms.

B may be a carbonyl group or a methylene chain bond species which may besubstituted by a C₁₋₄ alkyl group.

X may be a chlorine atom or a bromine atom.

Y¹ may, for example, be a hydrogen atom, a chlorine atom, a bromineatom, an iodine atom, a nitro group, an amino group, a methoxy group, anethoxy group, a n-propoxy group, an i-propoxy group, a n-butoxy group,an i-butoxy group, a sec-butoxy group or a t-butoxy group.

Y² may, for example, be a hydrogen atom, a chlorine atom, a bromineatom, an iodine atom, a hydroxyl group, a methyl group, an ethyl group,a n-propyl group, an i-propyl group, a n-butyl group, an i-butyl group,a sec-butyl group, a t-butyl group, a methoxy group, an ethoxy group, an-propoxy group, an i-propoxy group, a n-butoxy group, an i-butoxygroup, a sec-butoxy group or a t-butoxy group.

R⁴ and R⁵ are as follows:

(1) Each of them is a C₁₋₄ alkyl group such as a methyl group, an ethylgroup, a n-propyl group, an i-propyl group, a n-butyl group, an i-butylgroup, a sec-butyl group or a t-butyl group.

(2) R⁴ is a hydrogen atom, and R⁵ is --Z--At (wherein Z is a C₁₋₅alkylene chain, and Ar is an aromatic 6-membered ring which may containone or two nitrogen atoms). The aromatic 6-membered ring includes aphenyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a3-pyridazinyl group, a 4-pyridazinyl group, a 2-pyrimidinyl group, a4-pyrimidinyl group, a 5-pyrimidinyl group and a 2-pyrazinyl group.

(3) R⁴ and R⁵ together form a C₂₋₆ cyclic alkylene group, and they formtogether with the nitrogen atom to which they are bonded, an aziridinering, an azetidine ring, a pyrrolidine ring, a piperidine ring or ahomopiperidine ring.

(4) R⁴ and R⁵ form together with the adjacent nitrogen atom to whichthey are bonded, a 4-substituted piperazine ring of the formula:##STR8## or a 4-substituted piperidine ring of the formula: ##STR9##

R⁶ is a C₁₋₄ alkyl group or --COR¹⁰ (wherein R¹⁰ is a hydrogen atom or aC₁₋₄ alkyl group).

The C₁₋₄ alkyl group for R⁶ is preferably a methyl group and may have asubstituent. Such a substituent may, for example, be a C₁₋₄ alkyl group,a phenyl group which may be substituted by Y³ (wherein Y³ is a hydrogenatom, a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, an aminogroup, an N-formyl group or a C₁₋₄ alkylcarbonylamino group), ##STR10##(wherein each of R⁷ and R⁸ is a hydrogen atom, or R⁷ and R⁸ formtogether with the carbon atoms to which they are respectively bonded, abenzene ring, and each of A, B, C and D which are independent of oneanother, is a nitrogen atom or a carbon atom) and ##STR11## (wherein Y³is as defined above, and R⁹ is a C₁₋₄ alkyl group or a benzyl groupwhich may be substituted by a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group or ahalogen atom on the benzene ring). The number of such substituents maybe one or more.

Specific examples of R⁶ include a benzyl group which may have a halogenatom substituted at an optional position of the o-, m- or p-position onthe benzene ring, an α,α-diphenylmethyl group, a pyridylmethyl groupwhich may be substituted at an optional position of the 2-, 3- or4-position, a pyrimidylmethyl group, a pyrazylmethyl group, apyridazylmethyl group, a quinolylmethyl group, an isoquinolylmethylgroup, a quinoxalylmethyl group, a quinazolylmethyl group, abenzimidazolylmethyl group having a benzyl group which may besubstituted by a halogen atom on the benzene ring or by a C₁₋₄ alkylgroup at the N-position, and a combination of such aromatic rings, suchas an α,α-phenyl-pyridylmethyl group, an α,α-phenyl -pyrimidylmethylgroup, an α,α-phenyl-pyrazylmethyl group, an α,α-phenyl-pyridazylmethylgroup, an α,α-phenyl-quinolylmethyl group, anα,α-phenylisoquinolylmethyl group, an α,α-phenyl-isoquinoxalylmethylgroup or an α,α-phenyl-quinazolylmethyl group.

R¹¹ is a C₁₋₄ alkyl group, and this alkyl group may have substituents.The substituents include two types i.e. a phenyl group which may besubstituted by Y³ (wherein Y³ is as defined above) and a hydroxyl group.One of them or a plurality of each of them may be substituted.

Specific examples of R¹¹ include a benzyl group which may have a halogenatom substituted at an optional position of the o-, m- or p-position onthe benzene ring, an α,α-diphenylmethyl group and anα,α,α,α-hydroxydiphenylmethyl group. Preferred examples for each of R⁴and R⁵ include the 4-substituted piperazin-1-yl and 4-substitutedpiperidin-1-yl as described above.

In the foregoing description, n means normal, i iso, sec secondary, ttertiary, o ortho, m meta and p para.

The following compounds may be mentioned as preferred compounds amongthe compounds of the formula (I) of the present invention.

(1) A compound of the formula (I) wherein each of R² and R³ is ahydrogen atom, and Y¹ is a hydrogen atom, a halogen atom, a nitro groupor a C₁₋₄ alkoxy group.

(2) A compound of the formula (I) as defined in the above (1) wherein R⁴and R⁵ form together with the adjacent nitrogen atom to which they arebonded, a 4-substituted piperazine ring of the formula: ##STR12##wherein R¹² is a C₁₋₄ alkyl group {this alkyl group may be substitutedby one or more substituents selected from a group of substituentsconsisting of a C₁₋₄ alkyl group, a phenyl group which may besubstituted by Y³ (wherein Y³ is a hydrogen atom, a halogen atom, a C₁₋₄alkyl group, a C₁₋₄ alkoxy group, an amino group, an N-formyl group or aC₁₋₄ alkylcarbonylamino group), ##STR13## (wherein each of R⁷ and R⁸ isa hydrogen atom, or R⁷ and R⁸ form together with the carbon atoms towhich they are bonded, a benzene ring, and each of A, B, C and D whichare independent of one another, is a nitrogen atom or a carbon atom) and##STR14## (wherein Y³ is as defined above, and R⁹ is a C₁₋₄ alkyl groupor a benzyl group which may be substituted by a C₁₋₄ alkyl group, a C₁₋₄alkoxy group or a halogen atom on the benzene ring)} or --COR¹⁰ (whereinR¹⁰ is a hydrogen atom or a C₁₋₄ alkyl group), or a 4-substitutedpiperidine ring of the formula: ##STR15## wherein R¹¹ is a C₁₋₄ alkylgroup {this alkyl group may be substituted by one or more substituentsselected from a group of substituents consisting of a phenyl group whichmay be substituted by Y³ (wherein Y³ is as defined above) and a hydroxylgroup}.

(3) A compound as defined in the above (2) wherein R⁴ and R⁵ formtogether with the adjacent nitrogen atom to which they are bonded, a4-substituted piperazine ring of the formula: ##STR16## wherein R¹³ is amethyl group {this methyl group may be substituted by one or moresubstituents selected from a group of substituents consisting of aphenyl group which may be substituted by Y³ (wherein Y³ is a hydrogenatom, a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, an aminogroup, an N-formyl group or a C₁₋₄ alkylcarbonylamino group), ##STR17##(wherein each of R⁷ and R⁸ is a hydrogen atom, or R⁷ and R⁸ formtogether with the carbon atoms to which they are bonded, a benzene ring,and each of A, B, C and D which are independent of one another, is anitrogen atom or a carbon atom) and ##STR18## (wherein Y³ is as definedabove, and R⁹ is a C₁₋₄ alkyl group or a benzyl group which may besubstituted by a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group or a halogenatom)} or --COR¹⁰ (wherein R¹⁰ is a hydrogen atom or a C₁₋₄ alkylgroup).

(4) A compound as defined in the above (3), wherein Y² is a halogen atomor a C₁₋₄ alkoxy group.

(5) A compound as defined in the above (4), wherein R⁴ and R⁵ formtogether with the adjacent nitrogen atom to which they are bonded, a4-substituted piperazine ring of the formula: ##STR19## wherein R¹⁴ is##STR20## (wherein Y⁴ is a hydrogen atom, a halogen atom, an aminogroup, an N-formyl group or a C₁₋₄ alkylcarbonylamino group), ##STR21##(wherein R¹⁵ is a benzyl group which may be substituted by a halogenatom).

The compounds of the formula (I) include optical isomers and stereoisomers based on from 1 to 5 asymmetric carbon atoms.

The compounds of the formula (I) of the present invention can beconverted to pharmaceutically acceptable non-toxic salts by means ofappropriate acids, as the case requires. The compounds of the formula(I) can be used for the purpose of the present invention either in thefree form or in the form of the pharmaceutically acceptable salts. Thesalts of such bases may, for example, be a mineral acid salt (such as ahydrochloride, a hydrobromide, a sulfate, a hydrogensulfate, a nitrate,a phosphate, a hydrogenphosphate or a dihydrogenphosphate), an organicacid salt (such as a formate, an acetate, a propionate, a succinate, amalonate, an oxalate, a maleate, a fumarate, a malate, a citrate, atartarate, a lactate, a glutamate, an aspartate, a picrate or acarbonate) and a sulfonic acid salt (such as a methane sulfonate,benzene sulfonate or a toluene sulfonate). These salts may be preparedby conventional methods, respectively.

Now, typical examples of the 3-(2H)-pyridazinone derivative of theformula (I) and its pharmaceutically acceptable salt of the presentinvention will be given in Table I. However, it should be understoodthat the present invention is by no means restricted by such specificexamples.

in Table I, n means normal, i iso, t tertiary, Me a methyl group, Et anethyl group, Pr a propyl group, Bu a butyl group, and Ph a phenyl group.

Q1 to Q42 in Table I are groups represented by the following formulas.##STR22##

                                      TABLE I                                     __________________________________________________________________________    No.                                                                              R.sup.1                                                                           R.sup.2                                                                          R.sup.3                                                                         X  Y.sup.1                                                                          Y.sup.2                                                                           OA    B  NR.sup.4 R.sup.5                               __________________________________________________________________________     1 H   H  H Br H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q10.HCl                                         2 H   H  H Cl Cl 4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q10.HCl                                         3 H   H  H Cl NO.sub.2                                                                         4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q10.HCl                                         4 H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q19.2HCl                                        5 H   H  H Br H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q19.2HCl                                        6 H   H  H Br H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q19.Q35                                         7 H   H  H Br H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q21.2HCl                                        8 H   H  H Br H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q21.Q35                                         9 H   H  H Br H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q21.H.sub.2 SO.sub.4                            10                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q21.2HCl                                        11                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q21.H.sub.2 SO.sub.4                            12                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q21.Q35                                         13                                                                              H   H  H Br H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q20.2HCl                                        14                                                                              H   H  H Br H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q20.Q35                                         15                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q20.2HCl                                        16                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q20.Q35                                         17                                                                              Et  H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q20.2HCl                                        18                                                                              H   H  H Br H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q10.HCl                                         19                                                                              H   H  H Cl Cl 4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q10.HCl                                         20                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q16.2HCl                                        21                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q17.2HCl                                        22                                                                              H   H  H Br H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q19.2HCl                                        23                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q19.2HCl                                        24                                                                              H   H  H Cl NO.sub.2                                                                         4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q19.2HCl                                        25                                                                              H   H  H Cl Cl 4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q19.2HCl                                        26                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q20.2HCl                                        27                                                                              Et  H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q20.2Q35                                        28                                                                              .sup.i Pr                                                                         H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q20.2Q35                                        29                                                                              H   H  H Cl NO.sub.2                                                                         4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q21.2HCl                                        30                                                                              H   H  H Cl Cl 4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q21.2HCl                                        31                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q37.HCl                                         32                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q16.HCl                                         33                                                                              H   H  H Br H  4-OMe                                                                             3-Q1  CO Q16.HCl                                         34                                                                              H   H  H Br H  4-OMe                                                                             3-Q1  CO Q23.2HCl                                        35                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q23.2HCl                                        36                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q19.Q35                                         37                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q19.HCl                                         38                                                                              H   H  H Br H  4-OMe                                                                             3-Q1  CO Q19.Q35                                         39                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q20.Q35                                         40                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q20.HCl                                         41                                                                              Et  H  H Cl H  4-OMe                                                                             3-Q1  CO Q20.Q36                                         42                                                                              .sup.i Pr                                                                         H  H Cl H  4-OMe                                                                             3-Q1  CO Q20.Q35                                         43                                                                              H   H  H Br H  4-OMe                                                                             3-Q1  CO Q20.Q35                                         44                                                                              H   H  H Br H  4-OMe                                                                             3-Q1  CO Q20.HCl                                         45                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CO Q23.2HCl                                        46                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CO Q16.HCl                                         47                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CO Q19.HCl                                         48                                                                              H   H  H Br H  4-OMe                                                                             3-Q3  CO Q19.HCl                                         49                                                                              H   H  H Cl H  4-OMe                                                                             3-Q4  CO Q19.HCl                                         50                                                                              CONH.sub.2                                                                        H  H Cl H  4-OMe                                                                             3-Q1  CO Q20.Q35                                         51                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q21.Q35                                         52                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CO Q20.Q35                                         53                                                                              H   H  H Cl H  4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q20.2Q35                                        54                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q19.2Q35                                        55                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q20.2Q35                                        56                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CO Q20.Q35                                         57                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q20.2Q35                                        58                                                                              H   H  H Cl H  4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q29.2Q35                                        59                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q29.2Q35                                        60                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q34.2Q35                                        61                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q29.Q35                                         62                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q27                                             63                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q27.Q35                                         64                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CO Q20.Q35                                         65                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q20.2Q35                                        66                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CO Q19.Q35                                         67                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CO Q29.Q36                                         68                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CO Q20.Q35                                         69                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CO Q20.Q35                                         70                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q29.2Q35                                        71                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q29.2Q35                                        72                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q34.2Q35                                        73                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CO Q34.Q35                                         74                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CO Q27                                             75                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q27.Q35                                         76                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q20.Q35                                         77                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q25.2Q35                                        78                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q24                                             79                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q25.Q35                                         80                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q26.Q35                                         81                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CH.sub.2                                                                         Q42                                             82                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q12.HCl                                         83                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q14.HCl                                         84                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q16.2HCl                                        85                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q18.2HCl                                        86                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q22.2HCl                                        87                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q23.3HCl                                        88                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q28.HCl                                         89                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q37.2HCl                                        90                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q39.HCl                                         91                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q40.3HCl                                        92                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q29.2HCl                                        93                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q30.3HCl                                        94                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q31.3HCl                                        95                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q32.3HCl                                        96                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q33.2HCl                                        97                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q24.3HCl                                        98                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q25.2HCl                                        99                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q26.2HCl                                       100                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q34.2HCl                                       101                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q19.2HCl                                       102                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q21.2HCl                                       103                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q23.3HCl                                       104                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q24.3HCl                                       105                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q25.2HCl                                       106                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q26.2HCl                                       107                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q28.HCl                                        108                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q29.3HCl                                       109                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q33.2HCl                                       110                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q34.2HCl                                       111                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q10.HCl                                        112                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q17.2HCl                                       113                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q19.2HCl                                       114                                                                              H   H  H Br H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q11.HCl                                        115                                                                              Me  H  H Br H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q11.HCl                                        116                                                                              H   Me H Br H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q11.HCl                                        117                                                                              H   H  H Br H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q17.2HCl                                       118                                                                              H   H  H Br NH.sub.2                                                                         4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q17.2HCl                                       119                                                                              H   H  H Br Br 4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q17.2HCl                                       120                                                                              H   H  H Br H  4-Cl                                                                              3-Q1  CH.sub.2                                                                         Q19.2HCl                                       121                                                                              H   H  H Br H  H   3-Q1  CH.sub.2                                                                         Q20.2HCl                                       122                                                                              H   H  H Br H  4-OEt                                                                             3-Q1  CH.sub.2                                                                         Q20.2HCl                                       123                                                                              H   H  H Br H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q22.2HCl                                       124                                                                              H   H  H Br H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q23.3HCl                                       125                                                                              H   H  H Br H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q38.2HCl                                       126                                                                              H   H  H Br H  4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q40.3HCl                                       127                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q9.HCl                                         128                                                                              H   H  Me                                                                              Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q9.HCl                                         129                                                                              H   H  H Cl Cl 4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q9.HCl                                         130                                                                              .sup.t Bu                                                                         H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q9.HCl                                         131                                                                              H   H  H Cl H  4-OH                                                                              3-Q2  CH.sub.2                                                                         Q9.HCl                                         132                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q13.HCl                                        133                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q14.HCl                                        134                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q15.HCl                                        135                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q28.HCl                                        136                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q41.HCl                                        137                                                                              H   H  H Br H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q12.HCl                                        138                                                                              .sup.i Pr                                                                         H  H Br H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q14.HCl                                        139                                                                              H   H  H Br H  4-Cl                                                                              3-Q2  CH.sub.2                                                                         Q14.HCl                                        140                                                                              H   H  H Br H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q18.2HCl                                       141                                                                              H   H  H Br H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q20.2HCl                                       142                                                                              H   H  H Br Br 4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q20.2HCl                                       143                                                                              H   Me H Br H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q20.2HCl                                       144                                                                              H   H  H Br H  4-OH                                                                              3-Q2  CH.sub.2                                                                         Q20.2HCl                                       145                                                                              H   H  H Br H  H   3-Q2  CH.sub.2                                                                         Q20.2HCl                                       146                                                                              H   H  H Br H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q21.2HCl                                       147                                                                              H   H  H Br H  4-OMe                                                                             2-Q2  CH.sub.2                                                                         Q21.2HCl                                       148                                                                              H   H  H Br H  4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q23.3HCl                                       149                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CH.sub.2                                                                         Q10.HCl                                        150                                                                              H   H  H Cl Cl 4-OMe                                                                             3-Q3  CH.sub.2                                                                         Q10.HCl                                        151                                                                              Et  H  H Cl H  4-OMe                                                                             3-Q3  CH.sub.2                                                                         Q10.HCl                                        152                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CH.sub.2                                                                         Q13.HCl                                        153                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CH.sub.2                                                                         Q15.2HCl                                       154                                                                              H   H  H Cl H  4-OEt                                                                             3-Q3  CH.sub.2                                                                         Q19.2HCl                                       155                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CH.sub.2                                                                         Q21.2HCl                                       156                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CH.sub.2                                                                         Q22.2HCl                                       157                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CH.sub.2                                                                         Q23.3HCl                                       158                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CH.sub.2                                                                         Q37.2HCl                                       159                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CH.sub.2                                                                         Q40.3HCl                                       160                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CH.sub.2                                                                         Q41.HCl                                        161                                                                              H   H  H Br H  4-OMe                                                                             3-Q4  CH.sub.2                                                                         Q9.HCl                                         162                                                                              H   H  H Br H  4-OMe                                                                             3-Q4  CH.sub.2                                                                         Q12.HCl                                        163                                                                              H   H  H Br H  4-OMe                                                                             3-Q4  CH.sub.2                                                                         Q14.HCl                                        164                                                                              H   H  H Br H  4-OMe                                                                             3-Q4  CH.sub.2                                                                         Q16.2HCl                                       165                                                                              H   H  H Br H  4-OMe                                                                             3-Q4  CH.sub.2                                                                         Q20.2HCl                                       166                                                                              H   H  H Br H  2-OMe                                                                             3-Q4  CH.sub.2                                                                         Q20.2HCl                                       167                                                                              H   H  H Br H  4-OMe                                                                             3-Q4  CH.sub.2                                                                         Q28.HCl                                        168                                                                              H   H  H Br H  4-OMe                                                                             3-Q4  CH.sub.2                                                                         Q39.HCl                                        169                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q11.HCl                                        170                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q13.HCl                                        171                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q16.2HCl                                       172                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q18.2HCl                                       173                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q19.2HCl                                       174                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q20.2HCl                                       175                                                                              H   H  H Cl H  4-OEt                                                                             3-Q5  CH.sub.2                                                                         Q20.2HCl                                       176                                                                              H   H  H Cl H  4-O.sup.t Bu                                                                      3-Q5  CH.sub.2                                                                         Q20.2HCl                                       177                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q23.3HCl                                       178                                                                              H   H  H Br H  4-OMe                                                                             3-Q6  CH.sub.2                                                                         Q10.HCl                                        179                                                                              .sup.i Pr                                                                         H  H Br H  4-OMe                                                                             3-Q6  CH.sub.2                                                                         Q14.HCl                                        180                                                                              H   H  H Br H  4-OMe                                                                             3-Q6  CH.sub.2                                                                         Q17.2HCl                                       181                                                                              H   H  H Br H  4-OMe                                                                             3-Q6  CH.sub.2                                                                         Q21.2HCl                                       182                                                                              H   H  H Br H  4-OMe                                                                             3-Q6  CH.sub.2                                                                         Q39.HCl                                        183                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q10                                            184                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q12                                            185                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q14                                            186                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q17.HCl                                        187                                                                              H   H  H Cl H  4-OH                                                                              3-Q1  CO Q20.HCl                                        188                                                                              H   H  H Cl H  4-Cl                                                                              3-Q1  CO Q20.HCl                                        189                                                                              H   H  H Cl NO.sub.2                                                                         4-OMe                                                                             3-Q1  CO Q20.HCl                                        190                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q21.HCl                                        191                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q23.2HCl                                       192                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q39                                            193                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q41                                            194                                                                              H   H  H Br H  4-OMe                                                                             3-Q1  CO Q11                                            195                                                                              H   H  H Br H  4-OMe                                                                             3-Q1  CO Q13                                            196                                                                              Me  H  H Br H  4-OMe                                                                             3-Q1  CO Q16.HCl                                        197                                                                              H   H  H Br H  4-Cl                                                                              3-Q1  CO Q19.HCl                                        198                                                                              H   H  H Br H  2-OMe                                                                             3-Q1  CO Q19.HCl                                        199                                                                              H   H  H Br NO.sub.2                                                                         4-OMe                                                                             3-Q1  CO Q19.HCl                                        200                                                                              H   H  H Br NH.sub.2                                                                         4-OMe                                                                             3-Q1  CO Q19.HCl                                        201                                                                              H   H  H Br H  4-OMe                                                                             3-Q1  CO Q21.HCl                                        202                                                                              H   Me H Br H  4-OMe                                                                             3-Q1  CO Q21.HCl                                        203                                                                              H   H  H Br H  4-OEt                                                                             3-Q1  CO Q21.HCl                                        204                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CO Q10                                            205                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CO Q14                                            206                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CO Q17.HCl                                        207                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CO Q19.HCl                                        208                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CO Q20.HCl                                        209                                                                              H   H  H Cl H  4-Cl                                                                              3-Q2  CO Q20.HCl                                        210                                                                              H   H  H Cl H  H   3-Q2  CO Q20.HCl                                        211                                                                              H   H  H Cl H  4-F 3-Q2  CO Q20.HCl                                        212                                                                              Et  H  H Cl H  4-OMe                                                                             3-Q2  CO Q20.HCl                                        213                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CO Q21.HCl                                        214                                                                              H   H  H Cl NO.sub.2                                                                         4-OMe                                                                             3-Q2  CO Q21.HCl                                        215                                                                              H   H  H Cl Cl 4-OMe                                                                             3-Q2  CO Q21.HCl                                        216                                                                              Me  H  H Cl H  4-OMe                                                                             3-Q2  CO Q21.HCl                                        217                                                                              H   H  H Cl H  4-OMe                                                                             2-Q2  CO Q21.HCl                                        218                                                                              H   H  H Cl H  4-OMe                                                                             3-Q2  CO Q22.HCl                                        219                                                                              H   H  H Br H  4-OMe                                                                             3-Q2  CO Q9                                             220                                                                              H   H  H Br H  4-OMe                                                                             3-Q2  CO Q15                                            221                                                                              H   H  H Br H  4-OMe                                                                             3-Q2  CO Q18.HCl                                        222                                                                              H   H  H Br H  4-OMe                                                                             3-Q2  CO Q20.HCl                                        223                                                                              H   H  H Br H  4-OMe                                                                             3-Q2  CO Q23.2HCl                                       224                                                                              H   H  H Br H  4-OMe                                                                             3-Q2  CO Q28                                            225                                                                              H   H  H Br H  4-OMe                                                                             3-Q2  CO Q37.HCl                                        226                                                                              H   H  H Br H  4-OMe                                                                             3-Q2  CO Q39                                            227                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CO Q11                                            228                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CO Q17.HCl                                        229                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CO Q20.HCl                                        230                                                                              H   H  H Cl Cl 4-OMe                                                                             3-Q3  CO Q20.HCl                                        231                                                                              H   H  H Cl NH.sub.2                                                                         4-OMe                                                                             3-Q3  CO Q20.HCl                                        232                                                                              H   H  Me                                                                              Cl H  4-OMe                                                                             3-Q3  CO Q20.HCl                                        233                                                                              H   H  H Cl Cl 4-Cl                                                                              3-Q3  CO Q20.HCl                                        234                                                                              H   H  H Br H  4-OMe                                                                             3-Q4  CO Q10                                            235                                                                              H   H  H Br H  4-OMe                                                                             3-Q4  CO Q12                                            236                                                                              H   H  H Br H  4-OMe                                                                             3-Q4  CO Q13                                            237                                                                              H   H  H Br H  4-OMe                                                                             3-Q4  CO Q18.HCl                                        238                                                                              H   H  H Br H  4-OMe                                                                             3-Q4  CO Q19.HCl                                        239                                                                              H   H  H Br H  4-OMe                                                                             3-Q4  CO Q21.HCl                                        240                                                                              H   H  H Br H  4-OMe                                                                             3-Q4  CO Q23.2HCl                                       241                                                                              H   H  H Br H  4-OMe                                                                             3-Q4  CO Q38.HCl                                        242                                                                              H   H  H Br H  4-OMe                                                                             3-Q4  CO Q40.2HCl                                       243                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CO Q9                                             244                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CO Q16.HCl                                        245                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CO Q19.HCl                                        246                                                                              H   H  H Cl Cl 4-OMe                                                                             3-Q5  CO Q19.HCl                                        247                                                                              H   H  H Cl H  4-O.sup.n Bu                                                                      3-Q5  CO Q19.HCl                                        248                                                                              H   H  H Cl H  2-OMe                                                                             3-Q5  CO Q19.HCl                                        249                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CO Q20.HCl                                        250                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CO Q21.HCl                                        251                                                                              H   H  H Cl NO.sub.2                                                                         4-OMe                                                                             3-Q5  CO Q21.HCl                                        252                                                                              H   H  H Cl H  4-Cl                                                                              3-Q5  CO Q21.HCl                                        253                                                                              Et  H  H Cl H  4-OMe                                                                             3-Q5  CO Q21.HCl                                        254                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CO Q23.2HCl                                       255                                                                              H   H  H Br H  4-OMe                                                                             3-Q6  CO Q10                                            256                                                                              H   H  H Br H  4-OMe                                                                             3-Q6  CO Q15                                            257                                                                              H   H  H Br H  4-OMe                                                                             3-Q6  CO Q18.HCl                                        258                                                                              H   H  H Br H  4-OMe                                                                             3-Q6  CO Q19.HCl                                        259                                                                              H   H  H Br H  4-OMe                                                                             3-Q6  CO Q20.HCl                                        260                                                                              H   H  H Br Br 4-OMe                                                                             3-Q6  CO Q20.HCl                                        261                                                                              H   H  H Br NH.sub.2                                                                         4-OMe                                                                             3-Q6  CO Q20.HCl                                        262                                                                              H   H  H Br H  4-OMe                                                                             3-Q6  CO Q21.HCl                                        263                                                                              H   H  H Br H  4-Cl                                                                              3-Q6  CO Q21.HCl                                        264                                                                              .sup.i Bu                                                                         H  H Cl H  4-OMe                                                                             3-Q6  CO Q19.HCl                                        265                                                                              H   H  H Cl H  4-OMe                                                                             3-Q6  CO Q20.HCl                                        266                                                                              H   H  H Cl Cl 4-OMe                                                                             3-Q6  CO Q20.HCl                                        267                                                                              H   H  H Cl H  4-OMe                                                                             3-Q6  CO Q21.HCl                                        268                                                                              H   H  H Cl H  4-OMe                                                                             3-Q6  CO Q23.2HCl                                       269                                                                              H   H  H Cl H  4-OMe                                                                             3-Q6  CO Q37.HCl                                        270                                                                              H   H  H Cl H  4-OMe                                                                             3-Q6  CO Q41                                            271                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q21.2HCl                                       272                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q23.3HCl                                       273                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q24.3HCl                                       274                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q25.2HCl                                       275                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q26.2HCl                                       276                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q27.2HCl                                       277                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q28.HCl                                        278                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q29.3HCl                                       279                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q33.2HCl                                       280                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q34.2HCl                                       281                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q10.HCl                                        282                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q17.2HCl                                       283                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q19.2HCl                                       284                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q21.2HCl                                       285                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q23.3HCl                                       286                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q24.3HCl                                       287                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q25.2HCl                                       288                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q26.2HCl                                       289                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q27.HCl                                        290                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q28.HCl                                        291                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q29.3HCl                                       292                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q33.2HCl                                       293                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q34.2HCl                                       294                                                                              H   H  H Cl H  4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q10.HCl                                        295                                                                              H   H  H Cl H  4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q17.2HCl                                       296                                                                              H   H  H Cl H  4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q19.2HCl                                       297                                                                              H   H  H Cl H  4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q21.2HCl                                       298                                                                              H   H  H Cl H  4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q23.3HCl                                       299                                                                              H   H  H Cl H  4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q24.3HCl                                       300                                                                              H   H  H Cl H  4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q25.2HCl                                       301                                                                              H   H  H Cl H  4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q26.2HCl                                       302                                                                              H   H  H Cl H  4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q27.HCl                                        303                                                                              H   H  H Cl H  4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q28.HCl                                        304                                                                              H   H  H Cl H  4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q33.2HCl                                       305                                                                              H   H  H Cl H  4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q34.2HCl                                       306                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q24.HCl                                        307                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q25.2HCl                                       308                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q26.HCl                                        309                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q33.HCl                                        310                                                                              H   H  H Cl H  4-OMe                                                                             3-Q1  CO Q34.HCl                                        311                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CO Q20.HCl                                        312                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CO Q21.HCl                                        313                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CO Q24.2HCl                                       314                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CO Q25.HCl                                        315                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CO Q26.HCl                                        316                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CO Q27                                            317                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CO Q28                                            318                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CO Q29.2HCl                                       319                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CO Q33.HCl                                        320                                                                              H   H  H Cl H  4-OMe                                                                             3-Q3  CO Q34.HCl                                        321                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CO Q24.2HCl                                       322                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CO Q25.HCl                                        323                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CO Q26.HCl                                        324                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CO Q27                                            325                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CO Q28                                            326                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CO Q29.2HCl                                       327                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CO Q53.HCl                                        328                                                                              H   H  H Cl H  4-OMe                                                                             3-Q5  CO Q54.HCl                                        329                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CO Q10                                            330                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CO Q16.HCl                                        331                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CO Q19.HCl                                        332                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CO Q21.HCl                                        333                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CO Q23.2HCl                                       334                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CO Q24.2HCl                                       335                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CO Q25.2HCl                                       336                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CO Q26.2HCl                                       337                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CO Q27                                            338                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CO Q28                                            339                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CO Q29.2HCl                                       340                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CO Q33.HCl                                        341                                                                              H   H  H Cl H  4-OMe                                                                             3-Q7  CO Q34.HCl                                        342                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q10                                            343                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q16.HCl                                        344                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q19.HCl                                        345                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q21.HCl                                        346                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q23.3HCl                                       347                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q24.3HCl                                       348                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q25.2HCl                                       349                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q26.2HCl                                       350                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q29.2HCl                                       351                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q33.HCl                                        352                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CH.sub.2                                                                         Q34.HCl                                        353                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q10                                            354                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q16.HCl                                        355                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q19.HCl                                        356                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q20.2HCl                                       357                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q21.2HCl                                       358                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q23.3HCl                                       359                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q24.3HCl                                       360                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q25.2HCl                                       361                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q26.2HCl                                       362                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q27.HCl                                        363                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q28.HCl                                        364                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q2  CH.sub.2                                                                         Q33.2HCl                                       365                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q10                                            366                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q16.HCl                                        367                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q19.HCl                                        368                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q21.2HCl                                       369                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q23.3HCl                                       370                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q24.3HCl                                       371                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q25.2HCl                                       372                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q26.2HCl                                       373                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q27.HCl                                        374                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q28.HCl                                        375                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q29.3HCl                                       376                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q33.2HCl                                       377                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CH.sub.2                                                                         Q34.2HCl                                       378                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q10                                            379                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q16.2HCl                                       380                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q19.2HCl                                       381                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q20.2HCl                                       382                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q21.2HCl                                       383                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q23.3HCl                                       384                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q24.3HCl                                       385                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q25.2HCl                                       386                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q26.2HCl                                       387                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q27.HCl                                        388                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q28.HCl                                        389                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q29.3HCl                                       390                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q33.2HCl                                       391                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CH.sub.2                                                                         Q34.2HCl                                       392                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q10                                            393                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q16.2HCl                                       394                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q19.2HCl                                       395                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q20.2HCl                                       396                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q21.2HCl                                       397                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q23.3HCl                                       398                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q24.3HCl                                       399                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q26.2HCl                                       400                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q27.HCl                                        401                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q28.HCl                                        402                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q29.3HCl                                       403                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q33.2HCl                                       404                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q8  CH.sub.2                                                                         Q34.2HCl                                       405                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CO Q10                                            406                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CO Q16.2HCl                                       407                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CO Q21.2HCl                                       408                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CO Q23.2HCl                                       409                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CO Q24.3HCl                                       410                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CO Q25.2HCl                                       411                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CO Q26.2HCl                                       412                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CO Q27                                            413                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CO Q28                                            414                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q1  CO Q33.2HCl                                       415                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q3  CO Q10                                            416                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q3  CO Q16.HCl                                        417                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q3  CO Q19.HCl                                        418                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q3  CO Q20.HCl                                        419                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q3  CO Q21.2HCl                                       420                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q3  CO Q23.2HCl                                       421                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q3  CO Q24.3HCl                                       422                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q3  CO Q25.2HCl                                       423                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q3  CO Q26.2HCl                                       424                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q3  CO Q27                                            425                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q3  CO Q28                                            426                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q3  CO Q29.3HCl                                       427                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q3  CO Q33.2HCl                                       428                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q3  CO Q34.2HCl                                       429                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CO Q10                                            430                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CO Q16.HCl                                        431                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CO Q19.HCl                                        432                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CO Q21.2HCl                                       433                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CO Q23.2HCl                                       434                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CO Q24.3HCl                                       435                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CO Q25.2HCl                                       436                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CO Q26.2HCl                                       437                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CO Q27                                            438                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CO Q28                                            439                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CO Q29.3HCl                                       440                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CO Q33.2HCl                                       441                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q5  CO Q34.2HCl                                       442                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CO Q10                                            443                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CO Q16.HCl                                        444                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CO Q19.HCl                                        445                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CO Q21.2HCl                                       446                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CO Q23.2HCl                                       447                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CO Q24.3HCl                                       448                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CO Q25.2HCl                                       449                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CO Q26.2HCl                                       450                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CO Q27                                            451                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CO Q28                                            452                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CO Q29.3HCl                                       453                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CO Q33.2HCl                                       454                                                                              H   H  H Cl OEt                                                                              4-OMe                                                                             3-Q7  CO Q34.2HCl                                       455                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q10                                            456                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q17.2HCl                                       457                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q19.2HCl                                       458                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q20.2HCl                                       459                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q21.2HCl                                       460                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q23.2HCl                                       461                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q24.2HCl                                       462                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q25.2HCl                                       463                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q26.2HCl                                       464                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q27.HCl                                        465                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q28.HCl                                        466                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q29.3HCl                                       467                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q33.2HCl                                       468                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q34.2HCl                                       469                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q2  CO Q10                                            470                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q2  CO Q17.2HCl                                       471                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q2  CO Q19.2HCl                                       472                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q2  CO Q20.2HCl                                       473                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q2  CO Q21.2HCl                                       474                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q2  CO Q23.2HCl                                       475                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q2  CO Q24.2HCl                                       476                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q2  CO Q25.2HCl                                       477                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q2  CO Q26.2HCl                                       478                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q2  CO Q27.HCl                                        479                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q2  CO Q28.HCl                                        480                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q2  CO Q29.3HCl                                       481                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q2  CO Q33.2HCl                                       482                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q2  CO Q34.2HCl                                       483                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q10                                            484                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q17.2HCl                                       485                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q19.2HCl                                       486                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q20.2HCl                                       487                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q21.2HCl                                       488                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q23.2HCl                                       489                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q24.2HCl                                       490                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q25.2HCl                                       491                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q26.2HCl                                       492                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q27.HCl                                        493                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q28.HCl                                        494                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q29.3HCl                                       495                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q33.2HCl                                       496                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q34.2HCl                                       497                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q10                                            498                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q17.2HCl                                       499                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q19.2HCl                                       500                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q20.2HCl                                       501                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q21.2HCl                                       502                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q23.2HCl                                       503                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q24.2HCl                                       504                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q25.2HCl                                       505                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q26.2HCl                                       506                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q27.HCl                                        507                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q28.HCl                                        508                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q29.3HCl                                       509                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q33.2HCl                                       510                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q34.2HCl                                       511                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q8  CO Q10                                            512                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q8  CO Q17.2HCl                                       513                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q8  CO Q19.2HCl                                       514                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q8  CO Q20.2HCl                                       515                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q8  CO Q21.2HCl                                       516                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q8  CO Q23.2HCl                                       517                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q8  CO Q24.2HCl                                       518                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q8  CO Q26.2HCl                                       519                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q8  CO Q27.HCl                                        520                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q8  CO Q28.HCl                                        521                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q8  CO Q29.3HCl                                       522                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q8  CO Q33.2HCl                                       523                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q8  CO Q34.2HCl                                       524                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q10                                            525                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q17.HCl                                        526                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q19.HCl                                        527                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q21.HCl                                        528                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q23.2HCl                                       529                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q27                                            530                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q28                                            531                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q29.3HCl                                       532                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q33.2HCl                                       533                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q1  CO Q34.2HCl                                       534                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q3  CO Q10                                            535                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q3  CO Q17.HCl                                        536                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q3  CO Q19.HCl                                        537                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q3  CO Q20.HCl                                        538                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q3  CO Q21.HCl                                        539                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q3  CO Q23.2HCl                                       540                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q3  CO Q24.2HCl                                       541                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q3  CO Q25.HCl                                        542                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q3  CO Q26.HCl                                        543                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q3  CO Q27                                            544                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q3  CO Q28                                            545                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q3  CO Q29.2HCl                                       546                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q3  CO Q33.HCl                                        547                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q3  CO Q34.HCl                                        548                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q10                                            549                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q17.HCl                                        550                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q19.HCl                                        551                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q20.HCl                                        552                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q21.HCl                                        553                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q23.2HCl                                       554                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q24.2HCl                                       555                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q25.HCl                                        556                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q26.HCl                                        557                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q27                                            558                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q28                                            559                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q29.2HCl                                       560                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q33.HCl                                        561                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q5  CO Q34.HCl                                        562                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q10                                            563                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q17.HCl                                        564                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q3  CO Q19.HCl                                        565                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q20.HCl                                        566                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q21.HCl                                        567                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q23.2HCl                                       568                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q24.2HCl                                       569                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q25.HCl                                        570                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q26.HCl                                        571                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q27                                            572                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q28                                            573                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q29.2HCl                                       574                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q33.HCl                                        575                                                                              H   H  H Cl O.sup.i Pr                                                                       4-OMe                                                                             3-Q7  CO Q34.HCl                                        __________________________________________________________________________

Now, methods for producing the compounds of the present invention willbe described.

The 3(2H)-pyridazinone derivatives of the formula (I) and theirpharmaceutically acceptable salts of the present invention can beproduced, for example, by the methods represented by the followingreaction formulas (1) to (7). ##STR23## wherein R¹, R², R³, R⁴, R⁵, X,Y¹,Y², A and B are as defined above.

The production method according to the reaction formula (1) is a methodin which a 4,5-dihalo-3(2H)-pyridazinone compound of the formula (II)and a ω-aminoalkyleneoxy- or ω-aminocarbonylalkyleneoxy-substitutedbenzylamine derivative of the formula (III) or its salt are reactedoptionally in the presence of a dehydrohalogenating agent in an inertsolvent to produce the compound of the formula (I) of the presentinvention.

In the above reaction formula (1), a position isomer of the compound ofthe formula (I) i.e. a compound of the formula (IV) having anoxybenzylamino group substituted at the 4-position: ##STR24## whereinR¹, R², R³, R⁴, R⁵, X, Y¹, Y², A and B are as defined above, will formas a by-product. The production ratios of the compounds of the formulas(I) and depend primarily on the polarity of the solvent used.

Namely, when a solvent of high polarity is used, the production ratio ofthe compound of the formula (I) of the present invention tends to behigh. Accordingly, as a solvent suitable for efficiently producing thecompound of the formula (I) of the present invention while suppressingside-reaction for the production of the compound of the formula (IV), anether type solvent (such as tetrahydrofuran or 1,4-dioxane), an amidetype solvent (such as formamide, N,N-dimethylformamide,N,N-dimethylacetamide or N-methylpyrrolidone), acetonitrile,dimethylsulfoxide, an alcohol type solvent (such as methanol, ethanol orpropanol), an organic amine type solvent (such as pyridine,triethylamine, N,N-dimethylaminoethanol or triethanolamine) or water, ora solvent mixture thereof, may be mentioned. For separation andpurification of the compound of the formula (I) of the present inventionfrom the above mixture of the compound of the formula (I) and thecompound of the formula (IV), conventional methods per se known inorganic syntheses, such as fractional recrystallization or variouschromatography employing silica gel, may be employed.

During the reaction between the compound of the formula (II) and thecompound of the formula (III), hydrogen chloride or hydrogen bromide isgenerated. It is usually possible to improve the yield by adding to thereaction system a dehydrohalogenating agent which traps such a hydrogenhalide.

Any dehydrohalogenating agent may be used so long as it does notadversely affect the reaction and is capable of trapping a hydrogenhalide. As such a dehydrohalogenating agent, an inorganic base such aspotassium carbonate, sodium carbonate, potassium hydrogen carbonate, orsodium hydrogen carbonate, or an organic base such asN,N-dimethylaniline, N,N-diethylaniline, trimethylamine, triethylamine,N,N-dimethylaminoethanol, N-methylmorpholine, pyridine or2,6-dimethyl-4-N,N-dimethylaminopyridine, may be mentioned.

Otherwise, the starting material benzylamine derivative of the formula(III) may be used in an excessive amount as the dehydrohalogenatingagent. This gives an improved yield in many cases.

The reaction temperature may be usually within a range of from 10° C. tothe boiling point of the solvent used for the reaction.

The molar ratio of the starting materials may optionally be set.However, the benzylamine derivative of the formula (III) or its salt maybe used usually in an amount of from 1 to 10 mols, preferably from 1.2to 5 mols, relative to one mol of the 4,5-dihalo-3(2H)-pyridazinonederivative of the formula (II).

The 4,5-dihalo-3(2H)-pyridazinone derivative of the formula (II) can beproduced, for example, by utilizing or applying a conventional organicreaction or the following conventional production method. Namely, theone wherein the substituent Y¹ at the 6-position is a hydrogen atom, canbe prepared by the method disclosed in reference (a) and (b), and theone wherein the substituent Y¹ is a halogen atom, a nitro group, anamino group or an alkoxy group, can be prepared by the method disclosedin reference (c).

The ω-aminoalkyleneoxy- or ω-aminocarbonylalkyleneoxy-substitutedbenzylamine derivative of the formula (III) or its salt in the reactionformula (1) can be produced, for example, by methods of the followingreaction schemes (A) to (E) by utilizing or applying the methodsdisclosed in reference (a). ##STR25## wherein hal is a leaving groupsuch as a chlorine atom, a bromine atom, an iodine atom, amethanesulfonyloxy group or a p-toluenesulfonyloxy group, R is ahydrogen atom, a hydroxyl group, a C₁₋₄ alkyl group or a C₁₋₄ alkoxygroup, and R², R³, R⁴, R⁵, Y², A and B are as defined above. ##STR26##wherein T is an amino-protecting group such as a benzyloxycarbonylgroup, a t-butoxycarbonyl group, a formyl group, an acetyl group, abenzoyl group, a methoxycarbonyl group or an ethoxycarbonyl group, andR², R³, R⁴, R⁵, Y², A, B, R and hal are as defined above. ##STR27##wherein R⁹ is a hydrogen atom or a lower alkyl group, and R², R³, R⁴,R⁵, Y², A, T and hal are as defined above. ##STR28## wherein R¹⁰ is ahydrogen atom or a C₁₋₄ alkyl group, hal' is a leaving group within thesame scope as hal defined in the above reaction scheme (A), but it is asubstituent having the same or low leaving property as compared with halin the particular combination, and R², R³, R⁴, R⁵, Y², A, T and hal areas defined above. ##STR29## wherein D is a C₁₋₄ alkylene group, and R²,R3, R⁴, R⁵, Y² and hal are as defined above.

Reaction scheme (A) illustrates a method wherein a hydroxycarbonylderivative (IX) is used as the starting material, and firstly a compoundof the formula (VIII) is reacted to the phenol site to introduce thecorresponding alkoxy side chain, and then the carbonyl site is convertedto an amino group by reduction. Whereas, reaction scheme (B) illustratesa production method wherein this order in reaction scheme (A) isreversed. Reaction scheme (C) illustrates a method wherein theN-protected hydroxybenzylamine derivative of the formula (X) as anintermediate of the production route of scheme (B) is used as thestarting material, and the side chain of the phenol site thereof isstepwise extended, and from the ω-aminocarbonylalkyleneoxybenzylaminederivative of the formula (IIIa), its reduced product of the formula(IIIb) having the amide bond site of the formula (IIIa) reduced, isproduced. Reaction scheme (D) illustrates a method for producing aω-aminoalkyleneoxybenzylamine derivative of the formula (IIIc)containing a branched methylene chain wherein B is substituted by alower alkyl group, among benzylamine derivatives of the formula (III).Reaction scheme (E) illustrates a method for producing a compound of theformula (IIId) wherein A is a methylene chain having a hydroxyl group,among the benzyl amine derivatives of the formula (III).

Using a readily available commercial starting material or a startingmaterial produced therefrom, an appropriate method may be selected foruse among the methods (A) to (E).

For the reaction of the hydroxycarbonyl derivative (IX) with (VIII) inscheme (A), conditions commonly employed for alkylating phenols maywidely be used. Usually, this reaction proceeds relatively swiftly byusing an inorganic base such as sodium carbonate, potassium carbonate,sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate orpotassium hydrogencarbonate in a ketone type solvent (such as acetone,methyl ethyl ketone or diethyl ketone), an amide type solvent(formamide, N,N-dimethylformamide, N,N-dimethylacetamide orN-methylpyrrolidone), an alcohol type solvent (such as methanol, ethanolor n-propanol) or water, or a solvent mixture thereof under heating to atemperature of from 40° to 150° C.

The subsequent reaction for conversion of the carbonyl group (the formylgroup or the ketone group) to an aminomethyl group can be accomplishedby subjecting a various amine of the formula RNH₂ to a condensationreaction to obtain an imino compound and then reducing this iminocompound. In this method, this imino compound may not be isolated andmay be formed in the reaction system and continuously subjected to thesubsequent reduction reaction. Such a method may be rather advantageousin many cases from the viewpoint of the yield or economy.

Here, production of a primary amine wherein R² is a hydrogen atom amongthe benzylamine derivatives of the formula (III), can be accomplished byusing an amine such as ammonia, hydroxylamine or O-alkylhydroxylamine asRNH₂ and reducing an imine thereby obtained.

For such a reduction, a hydrogenation reaction is widely used whereinRaney nickel, palladium-carbon or the like is used as the catalyst.Here, when an imine compound produced with the O-alkylhydroxylamine isused, the reaction can be conducted by using a metal hydride such assodium trifluoroacetoxyborohydride NaBH₃ (OCOCF₃)! or sodiumbis-methoxyethoxyaluminumhydride NaAlH₂ (OCH₂ CH₂ OCH₃)₂ !(Chemical andPharmaceutical Bulletin, vol. 26, p. 2897-2898, 1978).

The latter reduction method employing a metal hydride may sometimes beadvantageous for producing a compound containing in Y² and R⁴ or R⁵ ahalogen atom or a benzyl group which is relatively unstable under thehydrogenation reduction conditions, among the benzylamine derivatives ofthe formula (III). Whereas, for the production of a secondary aminewherein R² is a C₁₋₄ alkyl group among the benzylamine derivatives ofthe formula (III), the corresponding primary alkylamine of the formulaR₂ NH₂ may be used as RNH₂, and then in the reduction of an iminederivative obtainable by this condensation reaction, not only thereducing agent described with respect to the above method for producinga primary amine but also a much milder metal hydrogenation reducingagent such as sodium borohydride or sodium cyanoborohydride (NaCNBH₃)may be added as a reducing agent which can be suitably and most widelyemployed.

Reaction scheme (B) is a production route to obtain a benzyl amine ofthe formula (III) by reversely carrying out the reaction steps inreaction scheme (A). Accordingly, the conversion of the carbonyl groupto an aminomethyl group and the alkylation reaction of the phenol sitecan be conducted under the respective reaction conditions of theproduction method described with respect to scheme (A). According tothis route, a step of introducing a protecting group for abenzylaminonitrogen atom is required in the process. As the protectinggroup of the formula T to be used here, it is possible to employ a widerange of protecting groups for amino groups which are commonly used forusual peptide syntheses, such as a benzyloxycarbonyl group, at-butoxycarbonyl group, a formyl group, an acetyl group, a benzoylgroup, a methoxycarbonyl group and an ethoxycarbonyl group. There is nostrict limitation for the selection of a protecting group from suchvarious protecting groups. However, in some cases, it will be necessaryto properly select the protecting group to be employed or the conditionsfor removing it, depending upon the types of the substituents Y², B, R⁴and R⁵. For example, to produce a compound containing in Y² or R⁴ and R⁵a halogen atom or a benzyl group in the benzylamine (III), in somecases, it will be necessary to properly select the substituents and thereaction conditions so that the reaction for removing the protectinggroup can be efficiently and selectively proceeded even by a methodother than catalytic hydrogenation. To produce a benzylamine of theformula (III) wherein B is a carbonyl chain, a benzyloxycarbonyl groupor a t-butoxycarbonyl group is preferably employed in many cases, sinceremoval of the protecting group can thereby be facilitated under anon-hydrolyzing condition. Conventional reaction conditions may beemployed as the reaction conditions for the above-mentioned introductionof various protecting groups and removal of such protecting groups.

Reaction scheme (C) illustrates a method wherein using ahydroxybenzylamine of the formula (X) protected by a protecting group Tas a starting material, the ether side chain is stepwise extended toobtain a compound of the formula (IIIa) wherein B is a carbonyl chainand a compound of the formula (IIIb) wherein B is a linear methylenechain obtained by reducing the carbonyl site, among benzylamines of theformula (III). In the reaction for forming an amide bond at the etherside chain site, when R⁹ is a hydrogen atom, dehydration condensationmethods which are commonly used for peptide syntheses can be widelyemployed. When an amine relatively rich in nucleophilic nature isemployed, it is possible to use an ester wherein R⁹ is a lower alkylgroup, and in such a case, it is usually possible to employ a conditionof heating in an inert solvent. As a reducing agent to be used forproducing a benzylamine of the formula (IIIb), a metal hydride reducingagent such as lithium aluminum hydride, may be mentioned. The alkylationof the phenol site and the reaction for removing the protecting group inother steps can be conducted under the respective correspondingreactions in schemes (A) and (B).

Reaction scheme (D) provides a method for producing anaminoalkyleneoxybenzylamine derivative of the formula (IIIc) wherein theα-carbon of the amino group at the terminal of the phenol side chain isa linear or lower alkyl-substituted methylene chain. For the step ofintroducing the amino group moiety, conventional reaction conditionscommonly employed in the substitution reaction of an alkylamine with analkyl halide, may be employed.

Reaction scheme (E) is designed to introduce a hydroxyl group to thephenol side chain in the formula (IIId) and provides a method wherein anepoxy group is introduced to the phenol side chain by the reaction withvarious epoxyalkylhalide compounds, and a compound of the formula (IIId)is produced by the reaction with various amines. ##STR30## wherein R¹ 'is a C₁₋₄ alkyl group, hal is a chlorine atom, a bromine atom or aniodine atom, and R², R³, R⁴, R⁵, X, Y¹, Y², A and B are as definedabove.

The reaction formula (2) illustrates a method for producing the2-position substituted pyridazinone product of the formula (I-b) as acompound of the present invention, by reacting a compound of the formula(I-a) which is a compound of the formula (I) of the present inventionwherein the 2-position of pyridazinone is a hydrogen atom, with ahalogeno derivative of the formula R¹ '-hal.

For this reaction, an inorganic base such as potassium carbonate, sodiumcarbonate, lithium carbonate, potassium hydrogencarbonate, sodiumhydrogencarbonate or lithium hydroxide, an organic base such astriethylamine or tri-n-propylamine, or a metal hydride or an organicmetal compound such as sodium hydride or n-butyl lithium, is used.

As the solvent for the reaction, a ketone type solvent (such as acetone,methyl ethyl ketone or diethyl ketone), an amide type solvent (such asformamide, N,N-dimethylformamide or N,N-dimethyl acetamide), an alcoholtype solvent (such as methanol or ethanol), water, or a solvent mixturethereof may be used, in the case where an inorganic or organic base isused. In the case where a metal hydride is used, an ether type solventis usually preferably employed.

As the reaction temperature, a temperature within a range of from 0° C.to the boiling point of the solvent may usually be employed in the casewhere an inorganic base or an organic base is used. In the case where ametal hydride or an organic metal compound is used, it is usuallypossible to employ a temperature within a range of from -78° C. to 60°C.

The molar ratio of the starting materials can optionally be set.However, the reactive derivative of the formula R¹ '-hal may be usedusually within a range of from 1 to 5 mols per mol of the compound ofthe formula (I-a).

For the isolation and purification of the desired product, conventionalmethods for organic syntheses such as recrystallization, variouschromatography employing silica gel and distillation, may be employed.##STR31## wherein R¹, R², R³, R⁴, R⁵, R⁹, X, Y¹, Y² and A are as definedabove.

The reaction formula (3) illustrates a method wherein a5-(ω-carboxyalkyleneoxy)benzylamino derivative or a5-(ω-alkoxycarbonylalkyleneoxy)benzylamino derivative of the formula (V)is subjected together with an amine compound of the formula (VI) to acondensation reaction by dehydration or dealcoholization to produce thecorresponding amide derivative of the formula (I-c).

For the condensation reaction in the case where R⁹ is a hydrogen atom,condensation methods commonly known for peptide syntheses can widely beemployed. For example, an acid chloride method and a mixed acidanhydride method as well as condensation methods employing condensingagents such as di-cyclohexylcarbodiimide, carbonyldiimidazole andN-hydroxysuccinimide can widely be employed, and a suitable condensationmethod may be selected for use depending upon the reactivity of theamine of the formula (VI). As the reaction conditions, conditionscommonly employed may be adopted.

In the case of a reaction with an amine rich in nucleophilic natureamong amines of the formula (VI), the condensation reaction will proceedeven with an ester wherein R⁹ is an alkyl group. In such a case, as thesolvent, any solvent may be employed without any particular restriction,so long as it is a solvent inert to the reaction. In many cases, thereaction may be conducted in the absence of a solvent. The reactiontemperature may be set within a range of from room temperature to 200°C., but it is common to conduct the reaction within a range of from 50°to 150° C. ##STR32## wherein R¹, R², R³, R⁴, R⁵, X, Y¹, Y², A, B and halare as defined above.

Reaction formula (4) illustrates a method for producing a compound ofthe formula (I) of the present invention by reacting a compound of theformula (VII) with a halogeno derivative of the formula (VIII).

For this reaction, an inorganic base such as potassium carbonate, sodiumcarbonate, lithium carbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate or lithium hydroxide, or an organic base such astriethylamine or tri-n-propylamine can usually be used.

As the solvent for the reaction, a ketone type solvent (such as acetone,methyl ethyl ketone or diethyl ketone), an amide type solvent (such asformamide, N,N-dimethylformamide or N,N-dimethylacetamide), an alcoholtype solvent (such as methanol or ethanol), water, or a solvent mixturethereof, may suitably be employed.

As the reaction temperature, it is usually possible to employ atemperature within a range of from 0° C. to the boiling point of thesolvent. ##STR33## wherein R¹, R², R³, R⁴, R⁵, R¹⁰, X, Y¹, Y², A and halare as defined above, and R⁷ is a hydrogen atom or a C₁₋₄ alkyl group.

Reaction formula (5) illustrates a method for producing an aminederivative of the formula (I-d) as a compound of the present invention,by reacting a compound of the formula (IX) obtainable by a methodcorresponding to the reaction formula (4), with an amine compound of theformula (VI).

This reaction can be conducted in the same manner as the methoddescribed for reaction formula (4). ##STR34## wherein R² ' is a C₁₋₄alkyl group, and R¹, R², R³, R⁴, R⁵, X, Y¹, Y², A, B and hal are asdefined above.

Reaction formula (6) illustrates a method for producing a compoundwherein R² is a C₁₋₄ alkyl group among the compounds of the presentinvention, by reacting a compound of the formula (I-e) which is acompound of the formula (I) of the present invention wherein R² is ahydrogen atom, with an alkyl halide of the formula R² '-hal in thepresence of a base.

As the organic solvent to be used, an amide type solvent such asdimethylformamide, an ether type solvent such as tetrahydrofuran ordiethyl ether, or an aprotic organic solvent such as n-hexane, benzeneor toluene, may usually be employed, and as the base, a metal hydridesuch as sodium hydride, n-butyl lithium, lithium diisopropylamide orsodium amide, may be employed to obtain good results.

As the reaction temperature, a temperature within a range of from -78°to 10° C. may be employed for the reaction with the base, and atemperature within a range of from -15° to 70° C. may be employed forthe reaction with the alkyl hydride. ##STR35## wherein R¹, R², R³, R⁴,R⁵, X, Y¹, Y², A, B and hal are as defined above.

Reaction formula (7) illustrates a method for producing a compound ofthe formula (I) of the present invention by reacting a3(2H)-pyridazinone of the formula (XI) having a --NHR² group at the5-position, with a benzyl halide derivative of the formula (XII) in thepresence of a base.

The reaction conditions may be similar to those described for reactionformula (6).

The manner of administration of the 3(2H)-pyridazinones of the formula(I) or their pharmaceutically acceptable salts of the present inventionmay be non-oral administration by an injection formulation(subcutaneous, intravenous, intramuscular or intraperitoneal injectionformulation), an ointment, a suppository or an aerosol, or oraladministration in the form of tablets, capsules, granules, pills,syrups, liquids, emulsions or suspensions.

The above pharmacological composition contains a compound of the presentinvention in an amount of from about 0.1 to 99.5% by weight, preferablyfrom about 0.5 to 95% by weight, based on the total weight of thecomposition.

To the compound of the present invention or to the compositioncontaining the compound of the present invention, otherpharmacologically active compounds may be incorporated.

The compound of the present invention may be formulated into variousformulations suitable for administration, in accordance withconventional methods commonly employed for the preparation ofpharmaceutical formulations.

Namely, tablets, capsules, granules or pills for oral administration,may be prepared by using an excipient such as sugar, lactose, glucose,starch or mannitol; a binder such as syrup, gum arabic, gelatin,sorbitol, tragacanth gum, methyl cellulose or polyvinylpyrrolidone; adisintegrant such as starch, carboxymethyl cellulose or its calciumsalt, crystal cellulose powder or polyethylene glycol; a gloss agentsuch as talc, magnesium or calcium stearate or silica; or a lubricantsuch as sodium laurate or glycerol.

The injections, solutions, emulsions, suspensions, syrups or aerosols,may be prepared by using a solvent for the active ingredient such aswater, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butyleneglycol, or polyethylene glycol; a surfactant such as a sorbitan fattyacid ester, a polyoxyethylene sorbitan fatty acid ester, apolyoxyethylene fatty acid ester, a polyoxyethylene ether ofhydrogenated castor oil or lecithin; a suspending agent such as a sodiumsalt of carboxymethyl cellulose, a cellulose derivative such as methylcellulose, or a natural rubber such as tragacanth gum or gum arabic; ora preservative such as a paraoxy benzoic acid ester, benzalkoniumchloride or a salt of sorbic acid.

Likewise, the suppositories may be prepared by using e.g. polyethyleneglycol, lanolin or coconut butter.

BEST MODE FOR CARRYING OUT THE INVENTION EXAMPLES (REFERENCE EXAMPLES,PREPARATION EXAMPLES, FORMULATION EXAMPLES AND TEST EXAMPLES)

Now, the present invention will be described in further detail withreference to Examples (including Reference Examples, PreparationExamples, Formulation Examples and Test Examples). However, it should beunderstood that the present invention is by no means restricted by thesespecific Examples. in Reference Examples, Preparation Examples or TableII, the symbols "NMR" and "MS" indicate "nuclear magnetic resonancespectrum" and "mass spectrum", respectively. NMR was measured in heavyhydrogen chloroform, unless otherwise specified.

In the MS data in Table II, only the principal peaks or typical fragmentpeaks are given.

Reference Example 1 ##STR36##

A mixture comprising 150 g of isovanillin, 93.2 g of sodium hydroxide,99 g of hydroxylamine sulfate, 600 ml of ethanol and 1500 ml of water,was refluxed under heating with stirring for 30 minutes and then cooledto 40° C. Then, 93.2 g of sodium hydroxide was added thereto, and 180 gof Raney alloy was added thereto over a period of 30 minutes. Themixture was stirred for one hour. insoluble matters were filtered offand washed with 100 ml of ethanol and 200 ml of water. The filtrate andthe washing solutions were put together, and 53.6 g of sodium hydroxidewas added thereto. Then, 186 g of benzyloxycarbonyl chloride wasdropwise added under cooling with ice. The mixture was stirred for 4hours. To this reaction solution, hydrochloric acid was added until thepH became from 1 to 2 and extracted with ethyl acetate. The organiclayer was washed with water and a saturated sodium chloride aqueoussolution and dried over anhydrous sodium sulfate. Then, the solvent wasdistilled off. The obtained residue was crystallized from diethyl etherto obtain 95.11 g of the above-identified compound as white crystals.

NMRδ: 7.34(s,5H), 6.79(s,3H), 5.78(s,1H), 5.12(br. s,2H), 4.25(d,2H),3.84(s,3H). MS(m/z): 287(M⁺), 196, 152, 137, 91(100%).

Reference Example 2 ##STR37##

A mixture comprising 150 g of isovanillin, 91 g of sodium hydroxide, 89g of hydroxylamine sulfate, 500 ml of ethanol and 1300 ml of water, wasrefluxed under heating with stirring for one hour and then cooled to 40°C. Then, 91 g of sodium hydroxide was added thereto, and 150 g of Raneyalloy was gradually added thereto at an internal temperature of from 30°to 50° C. The mixture was stirred for one hour. Insoluble matters werefiltered off and washed with 150 ml of ethanol and 150 ml of water. Thefiltrate and the washing solutions were put together and neutralizedwith concentrated hydrochloric acid under cooling until the pH became 8.Then, 1 l of acetonitrile was added thereto, and 215 g of di-t-butyldicarbonate was dropwise added thereto at room temperature over a periodof one hour. The mixture was stirred overnight. The organic layer waswashed with a saturated sodium chloride aqueous solution and then driedover anhydrous sodium sulfate. Then, the solvent was distilled off. Theobtained residue was purified by silica gel column chromatography (ethylacetate:benzene =1:5) to obtain 126 g of the above-identified compoundas oily substance.

NMRδ: 6.54-6.85(m,3H), 6.14-6.47(bs,1H), 4.92-5.34(m,1H), 4.09(d,2H),3.25(s,3H), 1.44(s,9H). MS(m/z): 153(M⁺ -100), 137(100%).

Reference Example 3 ##STR38##

A mixture comprising 20 g of N-benzyl oxycarbonyl-3-hydroxy-4-methoxybenzylamine, 17.43 g of ethyl bromoacetate, 14.43 gof potassium carbonate and 200 ml of 2-butanone, was refluxed underheating with stirring overnight. The mixture was cooled to roomtemperature. Then, inorganic substances were filtered off, and thefiltrate was distilled under reduced pressure. The obtained residue wasextracted with chloroform, and the organic layer was washed with waterand a saturated sodium chloride aqueous solution and then dried overanhydrous sodium sulfate. Then, the solvent was distilled off. Theobtained residue was crystallized from diethyl ether/n-hexane to obtain7.83 g of the above-identified compound as white crystals.

NMRδ: 7.33(s,5H), 6.85(s,3H), 5.12(s,2H), 4.63(s,2H), 4.26(d,2H),4.25(q,2H), 3.84(s,3H), 1.26(t,3H).

MS(m/z): 373(M⁺), 282, 239(100%), 210, 164, 136, 91.

In the same manner, the following compounds were prepared.

N-Benzyloxycarbonyl-3-ethoxycarbonylpropoxy-4-methoxybenzylamine

NMRδ:-7.25-7.55(m,5H), 6.72-7.06(m,3H), 5.14(s,2H), 3.71-4.52(m,10H),1.90-2.80(m,4H), 1.24(t,3H).

N-Benzyloxycarbonyl -3-ethoxycarbonylpentyloxy-4-methoxybenzylamine

Reference Example 4 ##STR39##

A mixture comprising 23.56 of N-benzyloxycarbonyl-3-ethoxycarbonylmethyloxy-4-methoxybenzylamine, 7.29 g of sodiumhydroxide, 300 ml of methanol and 30 ml of water, was stirred at 60° C.for one hour. The reaction solution was neutralized by an addition ofhydrochloric acid, and the solvent was distilled off under reducedpressure. Dilute hydrochloric acid was added to the obtained residue,and the mixture was extracted with chloroform. The extract layer waswashed with water and a saturated sodium chloride aqueous solution andthen dried over anhydrous sodium sulfate. The solvent was distilled off.The obtained residue was crystallized from diethyl ether/n-hexane toobtain 21.55 g of the above-identified compound as white crystals.

NMRδ: 7.34(s,5H), 6,84(s,3H), 5.13(s,3H), 4.62(s,2H), 4.25(d,2H),3.83(s,3H).

MS(m/z): 345(M⁺), 254, 210(100%), 91.

In the same manner, the following compounds were prepared.

N-Benzyloxycarbonyl-3-carboxypropyloxy-4-methoxybenzylamine

N-Benzyloxycarbonyl-3-carboxypentyloxy-4-methoxybenzylamine

Reference Example 5 ##STR40##

A mixture comprising 2 g of N-benzyloxycarbonyl-3-hydroxy-4-methoxybenzylamine, 20 ml of dimethylformamide, 1.4 g ofpotassium carbonate and 1.4 g of epibromohydrin, was stirred at 60° C.overnight After distilling off the solvent under reduced pressure, thereaction mixture was extracted with ethyl acetate. The obtained organiclayer was washed sequentially with an aqueous potassium carbonatesolution and with a saturated sodium chloride aqueous solution and thendried over anhydrous sodium sulfate. Then, the solvent was distilled offto obtain 2.6 g of the above-identified compound as oily substance.

NNMδ: 7.32(s,5H), 6.81(s,3H), 5.0-5.5(m,3H), 3.9-4.6(m,7H), 3.8(s,3H).

MS(m/z): 343(M⁺), 252, 208, 19(100%).

Reference Example 6 ##STR41##

A mixture comprising 5 g of N-benzyloxycarbonyl-3-carboxymethyloxy-4-methoxybenzylamine, 1.67 g of triethylamine and 40ml of tetrahydrofuran, was cooled with ice, and 1.79 g of ethylchloroformate dissolved in 10 ml of tetrahydrofuran, was dropwise addedthereto. The mixture was stirred for 2 hours. Then, 1.65 g ofmethylpiperazine dissolved in 0 ml of tetrahydrofuran, was added to thereaction solution, and the mixture was stirred at room temperature for4.5 hours. The precipitate was filtered off, and the filtrate wasdistilled under reduced pressure. Water was added to the obtainedresidue, and the mixture was extracted with chloroform. The extractsolution was washed with water and a saturated sodium chloride aqueoussolution and then dried over anhydrous sodium sulfate. Then, the solventwas distilled off. The obtained residue was crystallized from ethylacetate/diethyl ether/n-hexane to obtain 3.53 g of the above-identifiedcompound as white crystals.

NMRδ: 7.25(s,5H), 6.78(s,3H), 5.03(s,3H), 4.62(s,2H), 4.23(d,2H),3.78(s,3H), 3.40-3.72(m,4H), 2.11-2.60(m,7H).

MS(m/z): 427(M⁺), 292, 235, 141, 91(100%).

In the same manner, the following compounds were prepared.

N-Benzyloxycarbonyl-3-4-(3-pyridylmethyl)-piperazin-1yl!carbonylmethoxy-4-methoxybenzylamine

MS(m/z): 504(M⁺), 92(100%).

N-Benzyloxycarbonyl-3-(4-benzylpiperazin-1-yl)carbonylmethoxy-4-methoxybenzylamine

NMRδ: 7.15-7.43(m,10H), 6.7-6.92(m,3H), 4.85-5.24(m,3H), 4.62(s,2H),4.22(d,2H), 3.4-3.96(m,9H), 2.25-2.7(m,4H).

N-Benzyloxycarbonyl-3-4-(4-fluorobenzyl)-piperazin-1-yl!carbonylmethoxy-4-methoxybenzylamine

NMRδ: 6.60-7.50(m,12H), 5.0-5.5(m,3H), 4.62(s,2H), 4.22(d,2H),3.22-3.95(m,9H), 2.2-2.7(m,4H).

N-Benzyloxycarbonyl-3-4-(3-pyridylmethyl)-piperazin-1-yl!-carbonylpropoxy-4-methoxybenzylamine

MS(m/z): 532(M⁺), 92(100%).

N-Benzyloxycarbonyl-3-(4-benzylpiperazin-1-yl)-carbonylpropoxy-4-methoxybenzylamine

NMRδ: 7.0-7.40(m,10H), 6.60-6.90(m,3H), 5.50-5.5(m,3H), 3.22-4.37(m,3H),2.0-2.68(m,8H).

N-Benzyloxycarbonyl-3-(4-benzylpiperazin-1-yl)-carbonylpentyloxy-4-methoxybenzylamine

NMRδ: 7.0-7.35(m,10H), 6.60-6.80(m,3H), 5.0-5.50(m,3H),3.20-4.32(m,13H), 1.1-2.48(m,12H).

Reference Example 7 ##STR42##

A mixture comprising 2.4 g ofN-benzyloxycarbonyl-3-(2,3-epoxypropyloxy)-4-methoxybenzylamine, 30 mlof ethanol and 1.4 g of 4-fluorobenzyl-piperazine, was refluxed underheating with stirring overnight. The mixture was cooled to roomtemperature, and then the reaction solution was concentrated underreduced pressure and extracted with chloroform. The organic layer waswashed with an aqueous potassium carbonate solution and then dried overanhydrous sodium sulfate. Then, the solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:methanol=19:1) to obtain 2.6 g of theabove-identified compound.

NMRδ: 6.75-7.42(m,12H), 5.0-5.5(m,3H), 4.26(d,2H), 3.82-4.10(m,2H),3.77(s,3H), 3.20-3.60(m,3H), 2.20-2.85(m,10H).

MS(m/z): 537(M⁺), 207(100%), 109.

In the same manner, the following compounds were prepared.

N-Benzyloxycarbonyl-3-{4-(2-quinolylmethyl)-piperazin-1-yl}-β-hydroxypropyloxy!-4-methoxybenzylamine

NMRδ: 7.03-8.12(m,11H), 6.60-6.87(m,3H), 5.30-5.70(m,1H), 5.05(s,2H),3.22-4.37(m,11H), 2.22-2.80(m,10H).

N-Benzyloxycarbonyl-3-{4-(4-aminobenzyl)-piperazin-1-yl}-β-hydroxypropyloxy!-4-methoxybenzylamine

NMRδ: 6.45-7.41(m,12H), 5.40-6.78(m,1H), 5.04(s,2H), 3.50-4.38(m,11H),3.30 (s,2H), 2.10-2.80(m,8H).

Reference Example 8 ##STR43##

A mixture comprising 3.26 g ofN-benzyloxycarbonyl-3-(4-methylpiperazin-1-yl)-carbonylmethoxy-4-methoxybenzylamine,0.5 g of 5% palladium carbon and 70 ml of ethanol, was stirred at 60° C.for 6 hours in a hydrogen atmosphere and further at room temperatureovernight. Palladium carbon was filtered off, and then the filtrate wasdistilled off under reduced pressure to obtain 2.45 g of theabove-identified compound as slightly brown oil.

NMRδ: 6.88(s,3H), 4.74(s,2H), 3.50-4.10(m,9H), 2.29-2.58(m,7H),1.65(s,2H).

MS(m/z): 293(M⁺), 152, 299, 70(100%).

In the same manner, the following compounds were prepared.

3-4-(3-Pyridylmethyl)-piperazin-1-yl!carbonylmethoxy-4-methoxybenzylamine

MS(m/z): 370(M⁺), 92(100%).

3-(4-benzylpiperazin-1-yl)-carbonylmethoxy-4-methoxybenzylamine

MS(m/z): 369(M⁺), 91(100%).

3-4-(4-Fluorobenzyl)-piperazin-1-yl!carbonylmethoxy-4-methoxybenzylamine

MS(m/z): 387(M⁺), 109(100%).

3-4-(3-pyridylmethyl)-piperazin-1-yl!carbonylpropoxy-4-methoxybenzylamine

MS(m/z): 398(M⁺), 92(100%).

3-(4-methylpiperazin-1-yl)-carbonylpropoxy-4-methoxybenzylamine

MS(m/z): 321(M⁺), 99(100%).

3-(4-benzylpiperazin-1-yl)-carbonylpropoxy-4-methoxybenzylamine

MS(m/z): 397(M⁺), 91(100%).

3- 4-(4-Fluorobenzyl)-piperazin-1-yl)-1-oxo-2-methylethyloxy!-4-methoxybenzylamine

MS(m/z): 401(M⁺), 109(100%).

3-(4-Benzylpiperazin-1-yl)-carbonylpentyloxy-4-methoxybenzylamine

MS(m/z): 425(M⁺), 91(100%).

Preparation Example 1 ##STR44##

A mixture comprising 1.16 g of3-(4-methylpiperazin-1-yl)-carbonylmethoxy-4-methoxybenzylamine, 0.5 gof 4,5-dichloro-3(2H)-pyridazinone, 0.46 g of triethylamine, 10 ml ofethanol and 10 ml of water, was refluxed under heating with stirringovernight. The solvent was distilled off under reduced pressure, and anaqueous potassium carbonate solution was added to the residue. Themixture was extracted with chloroform. The extract solution was washedwith water and a saturated sodium chloride aqueous solution and thendried over anhydrous sodium sulfate. Then, the solvent was distilledoff. The obtained residue was purified by silica gel columnchromatography and then crystallized from chloroform/diethyl ether toobtain 0.61 g of the above-identified compound as white crystals.

NMRδ: 12.66(br. s,1H), 7.44(s,1H), 6.78(s,3H), 5.43(t,1H), 4.68(s,2H),4.39(d,2H), 3.77(s,3H), 3.30-3.75(m,4H), 2.0-2.60(m,7H).

MS(m/z): 421(M⁺), 386, 140, 99, 70(100%).

Reference Example 9 ##STR45##

A mixture comprising 0.3 g of 4-chloro-5-3-(4-methylpiperazin-1-yl)-carbonylmethoxy-4-methoxybenzylamino!-3(2H)-pyridazinone,2.0 g of potassium hydroxide, 10 ml of ethanol and 2 ml of water, wasrefluxed under heating with stirring overnight. The reaction solutionwas neutralized with an aqueous hydrochloric acid solution. Then, thesolvent was distilled off under reduced pressure. Then, water was addedto the obtained residue, and the mixture was extracted with chloroform.The extract solution was washed with water and a saturated sodiumchloride aqueous solution and then dried over anhydrous sodium sulfate.Then, the solvent was distilled off to obtain 212 mg of theabove-identified compound as white solid.

MS(m/z): 281(M⁺ --CHCO₂ H), 246, 209, 159, 145(100%), 116.

Preparation Example 2 ##STR46##

A mixture comprising 200 mg of4-chloro-5-(3-carboxymethyloxy-4-methoxbenzylamino)-3(2H)-pyridazinone,65 mg of triethylamine and 10 ml of N,N-dimethylformamide, was cooledwith ice, and 88 mg of isobutyl chloroformate was added thereto. Themixture was stirred at that temperature for one hour, and then 140 mg of3-picolylamine was added thereto. The mixture was stirred at roomtemperature overnight. The solvent was distilled off under reducedpressure, and water was added to the obtained residue. The mixture wasextracted with chloroform. The extract solution was washed with waterand a saturated sodium chloride aqueous solution and then dried overanhydrous sodium sulfate. Then, the solvent was distilled off. Theobtained residue was purified by silica gel column chromatography(eluent: chloroform/methanol=9/1) to obtain 129 mg of theabove-identified compound as white solid.

NMRδ: 8.35-8.58(m,2H), 7.81-8.33(m,1H), 7.72(s,1H), 7.45-7.60(m,2H),6.88(s,3H ), 6.40-6.80(m,1H), 4.31-4.62(m,6H), 3.75(s,3H).

MS(m/z): 429(M⁺), 394, 298, 137, 121, 107, 92(100%).

Reference Example 10 ##STR47##

A mixture comprising 20 g ofN-benzyloxycarbonyl-3-hydroxy-4-methoxybenzylamine, 14.43 g of potassiumcarbonate, 16.44 g of bromochloropropane and 200 ml of 2-butanone, wasrefluxed under heating with stirring for 16 hours. The mixture wascooled to room temperature. Then, inorganic substances were filteredoff, and the filtrate was distilled under reduced pressure. The obtainedresidue was extracted with chloroform, and the organic layer was washedwith water and a saturated sodium chloride aqueous solution and thendried over anhydrous sodium sulfate. Then, the solvent was distilledoff. The obtained residue was crystallized from diethyl ether/n-hexaneto obtain 23.19 g of the above-identified compound as white crystals.

NMRδ: 7.21(s,5H), 6.71(s,3H), 5.04(s,3H), 4.20(d,2H), 4.02(t,2H),3.75(s,3H), 3.67(t,2H), 1.94-2.47(m,2H).

MS(m/z): 363(M⁺), 316, 273(100%), 228, 152, 137, 125, 91.

In the same manner, the following compounds were prepared.

N-Benzyloxycarbonyl-3-(2-chloroethoxy)-4-methoxybenzylamine

N-Benzyloxycarbonyl-3-(2-diethylaminoethoxy)-4-methoxybenzylamine

Reference Example 11 ##STR48##

A mixture comprising 23.1 g ofN-benzyloxycarbonyl-3-(3-chloropropoxy)-4-methoxybenzylamine, 8.7 g ofN-formylpiperazine, 3,16 g off potassium carbonate, 0.95 g of sodiumiodide and 300 ml of N,N-dimethylformamide, was stirred at 80° C. for 16hours. The mixture was cooled to room temperature. Then, inorganicsubstances were filtered off, and the filtrate was distilled off underreduced pressure. The obtained residue was extracted with chloroform,and the organic layer was washed with water and a saturated sodiumchloride aqueous solution and then dried over anhydrous sodium sulfate.The solvent was distilled off to obtain 30.67 g of the above-identifiedcompound as slightly brown oil.

NMRδ: 7.97(s,1H), 7.32(s,5H), 6.8(s,3H), 5.36(brt,1H), 5.11(s,2H),4.26(d,2H), 4.02(t,2H), 3.81(s,3H), 3.12-3.66(m,4H), 78-2.78(m,8H).

MS(m/z): 44(M⁺), 383, 306, 155(100%), 128, 91.

In the same manner, the following compounds were prepared.

N-Benzyloxycarbonyl-3-(3-diethylaminopropoxy)-4-methoxybenzylamine

N-Benzyloxycarbonyl-3-2-(4-benzylpiperazin-1-yl)-ethoxy!-4-methoxybenzylamine

N-Benzyloxycarbonyl-3-2-{4-(4-chlorobenzyl)-piperazin-1-yl}-ethoxy!-4-methoxybenzylamine

N-Benzyloxycarbonyl-3- 2-{4-(4-fluorobenzyl)-piperazin-1-yl}-ethoxy!-4-methoxybenzylamine

N-Benzyloxycarbonyl-3-3-(4-benzylpiperazin-1-yl)-propoxy!-4-methoxybenzylamine

N-Benzyloxycarbonyl-3-3-(4-methylpiperazin-1-yl)-propoxy!-4-methoxybenzylamine

Reference Example 12 ##STR49##

A mixture comprising 30.4 g of N-benzyloxycarbonyl-3-3-(4-formylpiperazin-1-ly)-propoxy!-4-methoxybenzylamine, 3.1 g of 5%palladium carbon and 300 ml of ethanol, was stirred at 60° C. for 9hours under hydrogen atmosphere. Palladium carbon was filtered off, andthen the filtrate was distilled off under reduced pressure to obtain17.99 g of the above-identified compound as slightly brown oil.

NMRδ: 8.03(s,1H), 6.86(s,3H), 4.11(t,2H), 3.84(s,3H), 3.25-3.7(m,4H),2.30-2.82(m,4H), 1.82-2.30(m,4H).

MS(m/z): 307(M⁺), 292, 246, 171, 155, 125, 99(100%).

In the same manner, the following compounds were prepared.

3-(2-Diethylaminoethoxy)-4-methoxybenzylamine

3-(3-Diethylaminopropoxy)-4-methoxybenzylamine

3- 2-(4-Benzylpiperazin)-1-yl!-ethoxy-4-methoxybenzylpiperazine

3- 2-{4-(4-Chlorobenzyl)-piperazin-1-yl}-ethoxy!-4-methoxybenzylamine

3- 2-{4-(4-Fluorobenzyl)-piperazin-1-yl}-ethoxy!-4-methoxybenzylamine

3- 3-(4-benzylpiperazin-1-yl)-propoxy!-4-methoxybenzylamine

3- 3-(4-methylpiperazin-1-yl)-propoxy!-4-methoxybenzylamine

Preparation Example 3 ##STR50##

A mixture comprising 11.58 g of 3-3-(4-formylpiperazin-1-yl)-propoxy!-4-methoxybenzylamine, 5.0 g of4,5-dichloro-3(2H)-pyridazinone, 4.6 g of triethylamine, 50 ml ofn-propanol and 50 ml of water, was refluxed under heating with stirringfor 14 hours. The solvent was distilled off under reduced pressure, andan aqueous potassium carbonate solution was added to the obtainedresidue, and the mixture was extracted with chloroform. The organiclayer was washed with water and a saturated sodium chloride aqueoussolution and then dried over anhydrous sodium sulfate. Then, the solventwas distilled off, and the residue was purified by silica gel columnchromatography to obtain 6.21 g of the above-identified compound asslightly yellow white solid.

NMRδ: 12.49(br. s,1H), 8.06(s,1H), 7.65(s,1H), 6.88(s,3H), 5.37(t,1H),4.51(d,2H), 4.08(t,2H), 3.87(s,3H), 3.19-3.74(m,4H), 2.30-2.84(m,6H),1.76-2.30(m,2H).

Preparation Example 4 ##STR51##

A mixture comprising 10 g of 4-chloro-5-3-{3-(4-formylpiperazin-1-ly)-propoxy}-4-methoxybenzylamino!-3(2H)-pyridazinone,0.62 g of potassium hydroxide, 7 ml of ethanol and 7 ml of water, wasrefluxed under heating with stirring for 3 5 hours, and then 0.32 g ofpotassium carbonate and 570 mg of ethyl bromide were added thereto. Themixture was shirred at 60° C. for 4 hours. The solvent was distilled offunder reduced pressure and water was added to the obtained residue. Themixture was extracted with chloroform. The extract solution was washedwith water and a saturated sodium chloride aqueous solution and thendried over anhydrous sodium sulfate. Then, the solvent was distilledoff. The obtained residue was purified by silica gel columnchromatography to obtain 0.50 g of the above-identified compound asslightly brown solid.

NMRδ: 7.65(s,1H), 6.89(s,3H), 5.41(collapsed, 1H), 4.50(d,2H),4.08(t,2H), 3.87(s,3H), 1.73-3.10(m,14H), 1.08(t,3H).

MS(m/z): 435(M⁺), 365, 343, 206, 127(100%), 99.

In the same manner, the following compound was prepared.

4-Chloro-5-3-{3-(4-(4-fluorobenzyl)-piperazin-1-ly)-propoxy}-4-methoxybenzylamino!-3(2H)-pyridazinone

MS(M/z): 515(M⁺), 109(100%).

Preparation Example 5 ##STR52##

A mixture comprising 500 mg off 4-chloro-5-3-{(2-(4-(4-fluorobenzyl)-piperazin-1-ly)-ethoxy}-4-methoxybenzylamino!-3(2H)-pyridazinone,130 mg of ethyl bromide, 190 mg off potassium carbonate and 10 ml of2-butanone, was refluxed under heating with stirring for 5 hours.Inorganic substances were filtered off, and then the solvent wasdistilled off under reduced pressure. Water was added to the obtainedresidue, and the mixture was extracted with chloroform. The extractsolution was washed with water and a saturated sodium chloride aqueoussolution and then dried over anhydrous sodium sulfate. Then, the solventwas distilled off. The obtained residue was purified by silica gelcolumn chromatography (eluent: chloroform/ethanol=19/1) to obtain 429 mgof the above-identified compound as a colorless transparent stickysubstance.

NMRδ: 7.47(s,1H), 7.00-7.3(m,4H), 6.88(s,3H), 5.20(t,1H), 4.46(d,2H),4.14(t,2H), 4.12(q,2H), 3.85(s,3H), 3.47(s,2H), 2.73(t,2H),2.21-3.05(m,10H), 1.32(t,3H).

MS(m/z): 574(M⁺), 493, 273, 221, 192(100%), 164, 111, 84.

Reference Example 13 ##STR53##

A solution comprising 600 mg of N-quinolylmethylpiperazine and 20 ml ofdry tetrahydrofuran was cooled to -60° C., and a mixed solutioncomprising 330 mg of acetyl chloride and 5 ml of dry tetrahydrofuran,was dropwise added thereto over a period of 10 minutes. The mixture wasstirred at -60° C. for one hour, and 10 ml of water was added thereto.The mixture was stirred at room temperature for 20 minutes. The reactionsolution was distilled under reduced pressure and extracted withchloroform. The organic layer was washed with an aqueous potassiumcarbonate solution and dried over anhydrous sodium sulfate. Then, thesolvent was distilled off under reduced pressure to obtain 750 mg of theabove-identified compound as oily substance.

NMRδ: 7.32-8.20(m,6H), 4.01(s,2H), 3.20-3.90(m,6H), 2.30-2.74(m,4H).

MS(m/z): 143(M⁺ -160)

In the same manner, the following compounds were prepared.

1-Chloroacetyl-4-(4-chorobenzyl)-piperazine

MS(m/z): 286(M⁺), 125(100%).

1-Chloroacetyl-4- 1-(4-fluorobenzyl)-2-methylbenzoimidazole!-piperazine

NMRδ: 6.66-7.40(m,8H), 5.44(s,2H), 3.95(s,2H), 3.74(s,2H),3.04-3.60(m,4H), 2.24-2.66(m,4H).

1-Chloroacetyl-4-benzylpiperazine

MS(m/z): 252(M⁺), 91(100%).

1-Chloroacetyl-4-benzylpiperidine

MS(m/z): 251(M⁺), 91(100%).

1-Chloroacetyl-4-(t-butyloxycarbonylaminobenzyl)-piperazine

MS(m/z): 368(M⁺), 150(100%).

Reference Example 14 ##STR54##

mixture comprising 660 mg oft-butyloxycarbonyl-3-hydroxy-4-methoxybenzylamine, 10 ml ofdimethylformamide, 510 mg of potassium carbonate and 750 mg of1-chloroacetyl-4-(2-quinolylmethyl)-piperazine, was heated at 80° C.overnight with stirring. Insoluble matters were filtered off, and thenthe reaction solution was distilled under reduced pressure and extractedwith chloroform. The extract solution was washed with an aqueouspotassium carbonate solution and then purified by silica gel columnchromatography (ethyl acetate:methanol =19:1) to obtain 1.2 g of theabove-identified compound as oily substance.

NMRδ: 7.32-8.03(m,6H), 6.63-6.93(m,3H), 5.15-5.50(m,1H), 4.64(s,2H),4.16(d,2H), 3 38-3.93(m,9H), 2.30-2.73(m,4H), 1.43(s,9H).

MS(m/z): 520(M⁺), 144(100%).

In the same manner, the following compounds were prepared.

N-t-Butyloxycarbonyl-3-4-(4-chlorobenzyl)-piperazin-1-yl!-carbonylmethoxy-4-methoxybenzylamine

MS(m/z): 503(M⁺), 125(100%).

N-t-Butyloxycarbonyl-3-4-{1-(4-fluorobenzyl)-2-methylbenzoimidazole}-piperazin-1-yl!-carbonylmethoxy-4-methoxybenzylamine

NMRδ: 6.10-7.35(m,11H), 5.45(s,2H), 4.80-5.17(m,1H), 4.10(s,2H),4.15(d,2H), 3.76(s,3H), 3.70(s,12H), 3.26-3.65(m,4H), 2.27-2.65(m,4H).

N-t-Butyloxycarbonyl-3-(4-benzylpiperidin-1-yl)-carbonylmethoxy-4-methoxybenzylamine

MS(m/z): 468(M⁺), 91(100%).

N-t-Butyloxycarbonyl-3-(4-t-butyloxycarbonylaminobenzylpiperazin-1-yl)-carbonylmethoxy-4-methoxybenzylamine

MS(m/z): 585(M⁺), 150(100%).

Reference Example 15 ##STR55##

A mixture comprising 1.3 g of t-butyloxycarbonyl-3-4-(2-quinolylmethyl)-piperazin-1-yl!-carbonylmethoxy-4-methoxybenzylamine,4 ml of chloroform and 2.8 g of trifluoroacetic acid/was stirred at roomtemperature for one day. To the reaction solution, 50 ml of chloroformand 50 ml of 0.5N hydrochloric acid were added, and the mixture wasreversely extracted. The aqueous layer was adjusted to pH 12 with anaqueous sodium hydroxide solution and extracted with chloroform. Theorganic layer was washed with an aqueous potassium carbonate solutionand then dried over-anhydrous sodium sulfate. Then, the solvent wasdistilled off under reduced pressure to obtain 850 mg of theabove-identified compound as oily substance.

NMRδ: 7.39-8.20(m,6H), 6.72-7.0(m,3H), 4.7(s,2H), 3.40-4.00(m,11H),2.32-2.70(m,4H), 2.05(br. s,2H).

MS(m/z): 420(M⁺), 143(100%).

In the same manner, the following compounds were prepared.

3-4-(4-Chlorobenzyl)-piperazin-1-yl!-carbonylmethoxy-4-methoxybenzylamine

MS(m/z): 403(M⁺), 125(100%)

3-3-{4-(4-Fluorobenzyl)-piperazin-1-yl}-2,2-dimethylpropoxy!-4-methoxybenzylamine

MS(m/z): 429(M⁺), 109(100%).

3-(4-Benzylpiperizin-1-yl)-carbonylmethoxy-4-methoxybenzylamine

MS(m/z): 368(M⁺), 91(100%).

3-4-{1-(4-Fluorobenzyl)-2-benzimidazolylmethyl}-piperazin-1-yl!-carbonylmethoxy-4-methoxybenzylamine

MS(m/z): 517(M⁺), 109(100%).

Preparation Example 6 ##STR56##

A mixture comprising 2.4 g of 3-4-(2-quinolylmethyl)-piperazin-1-yl!-carbonylmethoxy-4-methoxybenzylamine,1 g of 4,5-dichloro-6-ethoxy-3(2H)-pyridazinone, 580 mg oftriethylamine, 10 ml of propanol and 10 ml of water, was refluxed underheating with stirring overnight. The solvent was distilled off underreduced pressure, and the residue was extracted with chloroform. Theorganic layer was washed with an aqueous potassium carbonate solutionand then dried over anhydrous sodium sulfate. Then, the solvent wasdistilled off. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:methanol =6:1→chloroform:methanol=12:1)and then crystallized from diethyl ether to obtain 1.5 g of theabove-identified compound as white crystals.

NMRδ: 7.40-8.28(m,6H), 6.72-7.05(m,3H), 4.62-5.40(m,5H),3.48-4.50(m,11H), 2.32-2.70(m,4H), 1.31(t,3H).

MS(m/z): 592(M⁺), 143(100%).

Reference Example 16 ##STR57##

A mixture comprising 9 g of 1-formyl-4-(4-nitrobenzyl)-piperazine, 180ml of methanol and 14.6 of nickel chloride hexahydrate, was cooled inice bath, and 4.6 g of sodium borohydride was slowly added thereto. Themixture was stirred at 0° C. for 30 minutes and further at roomtemperature for 30 minutes. The reaction solution was distilled offunder reduced pressure, and the residue was dissolved by an addition of200 ml of 10% hydrochloric acid, and adjusted to pH 10 with 28% aqueousammonia. Then, the mixture was extracted with ethyl acetate. The extractsolution was washed with a saturated sodium chloride aqueous solutionand then dried over anhydrous sodium sulfate. Then, the solvent wasdistilled off under reduced pressure. The residue was crystallized fromdiethyl ether to obtain 8.0 g of the above-identified compound as whitecrystals.

NMRδ: 7.82(s,1H), 6.97(d,2H), 6.47 (d,2H), 3.01-3.91(m,8H),2.11-2.48(m,4H).

MS(m/z): 263(M⁺), 218(100%).

Reference Example 17 ##STR58##

A mixture comprising 4 g of 1-formyl-4-aminobenzylpiperazine, 50 ml oftoluene and 4.8 g of di-t-butyl dicarbonate, was refluxed under heatingfor 5 hours. The reaction solution was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate:methanol=9:1) and then crystallized fromdiethyl ether to obtain 5.1 g of the above-identified compound as whitecrystals.

NMRδ: 7.87(s,1H), 6.97-7.42(m,5H), 3.15-3.65(m,6H), 2.15-2.57(m,4H),1.45(s,9H).

MS/m/z): 319(M⁺), 106(100%).

Reference Example 18 ##STR59##

4 g of 1-formyl-4-(t-butyloxycarbonylaminobenzyl)-piperazine wasdissolved in 50 ml of methanol, and an aqueous solution having 1.5 g ofsodium hydroxide dissolved in 10 ml of water, was added thereto. Themixture was heated at 60° C. for 5 hours. The reaction solution wasconcentrated under reduced pressure and then extracted with chloroform.The organic layer was washed with an aqueous potassium carbonatesolution and then dried over anhydrous sodium sulfate. Then, the solventwas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography (chloroform:methanol=5:1) and thencrystallized from diethyl ether to obtain 3.2 g of the above-identifiedcompound as white crystals.

NMRδ: 7.0-7.7(m,5H), 3.38(s,2H), 2.60-3.12(m,4H), 1.90-2.60(m,5H),1.50(s,9H).

MS(m/z): 291(M⁺), 206, 106(100%).

Preparation Example 7 ##STR60##

A mixture comprising 1.6 g of 3-4-(4-aminobenzyl)piperazin-1-yl!-carbonylmethoxy-4-methoxybenzylamine,770 mg of 4,5-dichloro-6-isopropoxy-3(2H)-pyridazinone, 460 mg oftrimethylamine and 20 ml of methanol, was refluxed under heating withstirring for 2 days. The solvent was distilled off under reducedpressure, and the residue was extracted with chloroform. The organiclayer was washed with an aqueous potassium carbonate solution and thendried over anhydrous sodium sulfate. Then, the solvent was distilledoff. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:methanol=9:1→chloroform:methanol=15:1) andthen crystallized from diethyl ether to obtain 1.6 g of theabove-identified compound as white crystals.

NMRδ: 6.55-7.15(m,7H), 4.45-5.33(m,6H), 3.13-3.88(m,11H),2.13-2.58(m,4H), 1.28(d,6H).

MS(m/z): 465(M⁺ 106), 430, 106(100%).

Preparation Example 8 ##STR61##

400 mg of 4-chloro-5-3-(4-aminobenzyl)piperazin-1-yl!-carbonylmethoxy-4-methoxybenzylamino-6-isopropoxy-3(2H)pyridazinonewas dissolved in 3 ml of phenyl formate. The solution was stirred atroom temperature overnight. The reaction solution was distilled underreduced pressure. Then, the obtained residue was purified by silica gelcolumn chromatography (chloroform:methanol=9:1) and then crystallizedfrom diethyl ether to obtain 380 mg of the above-identified compound aswhite crystals.

NMRδ: 11.75(br. s,1H), 8.2-8.85(m,2H), 6.75-7.62(m,7H), 4.58-5.30(m,6H),3.77(s,3H), 3.20-3.75(m,6H), 2.05-2.60(m,4H), 1.27(d,6H).

MS(m/z): 464(M⁺⁻ 134), 137(100%).

Preparation Example 9 ##STR62##

400 mg of 4-chloro-5-3-(4-aminobenzyl)-piperazin-1-yl!-carbonylmethoxy-4-methoxybenzylamino-6-isopropoxy-3(2H)-pyridazinonewas dissolved in 400 ml of pyridine, and 220 mg of acetic anhydride wasadded thereto. The mixture was stirred at room temperature for 2 hours.The solvent was distilled off under reduced pressure, and the residuewas extracted with chloroform. The organic layer was washed with anaqueous potassium carbonate solution and dried over anhydrous sodiumsulfate. Then, the solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography(chloroform:methanol=9:1) and then crystallized from diethyl ether toobtain 340 mg of the above-identified compound as white crystals.

NMRδ: 11.84(br. s,1H), 8.24(br. s,1H), 6.63-7.52(m,8H), 4.52-5.30(m,6H), 3.30-3.92 (m,9H), 2.0-2.62(m,7H), 1.25(d,6H).

MS(m/z): 613(M⁺ +H), 466.

Preparation Example 10 ##STR63##

To a mixed solution comprising 440 mg of 4-bromo-5-3-{2-(4-(4-chlorobenzyl)piperazin-1-yl)ethoxy}-4-methoxbenzylamino!-3(2H)-pyridazinoneand 5 ml of chloroform, 10% hydrochloric acid methanol was added untilthe ph became from 2 to 3, and the mixture was stirred at roomtemperature for 2 hours. Diethyl ether was added to the reactionsolution for crystallization to obtain 465 mg of the above-identifiedcompound as white crystals having a melting point of from 176°-183° C.

MS(m/z): 562(M⁺ -2HCl), 482, 238, 223(100%), 203, 125, 91.

Preparation Example 11 ##STR64##

A mixture comprising 163 mg of 4-bromo-5-3-{2-(4-(4-chlorobenzyl)-piperazin-1-yl)-ethoxy}-4-methoxybenzylamino!-3(2H)-pyridazinone,33 mg of fumaric acid and 4 ml of chloroform, was stirred at roomtemperature for 3 hours. Diethyl ether was added to the reactionsolution for crystallization to obtain 120 mg of the above-identifiedcompound as white crystals having a melting point of from 178°-185° C.

MS(m/z): 562(M⁺ --(CHCO₂ H)2), 482, 237, 223, 125(100%), 91.

Preparation Example 12 ##STR65##

A mixture comprising 700 mg of 4-bromo-5-3-{2-(4-(4-chlorobenzyl)-piperazin-1-yl)-ethoxy}-4-methoxybenzylamino!-3(2H)-pyridazinone,5 ml of methanol, 5 ml of chloroform and 140 mg of sulfuric acid, wasstirred at room temperature for 3 hours. The reaction solution wasdistilled off under reduced pressure, and the obtained residue wascrystallized from isopropyl ether/diethyl ether to obtain 800 mg of theabove-identified compound as white crystals having a melting point of158°-162° C.

MS(m/z): 482(M⁺ --Br--H₂ SO₄), 238, 223(100%), 125

Compounds prepared in accordance with the above Preparation Examples areshown in Table II. For the structures of these compounds, referenceshould be made to Compound Nos. shown in Table I. in the column at theright hand end in Table II, the number of applied Preparation Example isindicated.

                  TABLE II                                                        ______________________________________                                        Compound                                                                              Melting                                                               No.     point (°C.)                                                                     MS (m/z)          Example No.                                ______________________________________                                         1      Solid    424(M.sup.+ -HCl), 100(100%)                                                                    10                                          2      Solid    414(M.sup.+ -HCl), 100(100%)                                                                    10                                          3      193-196  425(M.sup.+ -HCl), 86(100%)                                                                     10                                          4      170-180  483(M.sup.+ -2HCl), 91(100%)                                                                    10                                          5      179-186  527(M.sup.+ -2HCl), 190(100%)                                                                   10                                          6      128-135  527(M.sup.+ -Q35), 203(100%)                                                                    11                                          7      176-183  See Example 10    10                                          8      178-185  See Example 11    11                                          9      158-162  See Example 12    12                                         10      159-163  517(M.sup.+ -2HCl), 125(100%)                                                                   10                                         11      179-184  517(M.sup.+ -H.sub.2 SO.sub.4), 125(100%)                                                       12                                         12      170-173  517(M.sup.+ -Q35), 125(100%)                                                                    11                                         13      180-187  545(M.sup.+ -2HCl), 207(100%)                                                                   10                                         14      184-188  545(M.sup.+ -Q35), 109(100%)                                                                    11                                         15      178-185  501(M.sup.+ -2HCl), 221(100%)                                                                   10                                         16      217-221  501(M.sup.+ -Q35), 109(100%)                                                                    11                                         17      157-162  573(M.sup.+ -2HCl), 221(100%)                                                                   10                                         18      62-70    438(M.sup.+ 2HCl), 86(100%)                                                                     10                                         19      78-89    428(M.sup.+ -HCl), 86(100%)                                                                     10                                         20      159-168  421(M.sup.+ -2HCl), 113(100%)                                                                   10                                         21      Solid    435(M.sup.+ -2HCl), 127(100%)                                                                   10                                         22      173-177  541(M.sup.+ -2HCl), 91(100%)                                                                    10                                         23      175-180  569(M.sup.+ -2HCl), 91(100%)                                                                    10                                         24      201-205  542(M.sup.+ -2HCl), 91(100%)                                                                    10                                         25      164-167  531(M.sup.+ -2HCl), 91(100%)                                                                    10                                         26      Solid    515(M.sup.+ -2HCl), 109(100%)                                                                   10                                         27      169-172  543(M.sup.+ -2Q35), 109(100%)                                                                   11                                         28      163-171  557(M.sup.+ -2Q35), 109(100%)                                                                   11                                         29      Solid    576(M.sup.+ -2HCl), 125(100%)                                                                   10                                         30       98-120  565(M.sup.+ -2HCl), 206(100%)                                                                   10                                         31      143-148  429(M.sup.+ -HCl), 92(100%)                                                                     10                                         32      170-180  421(M.sup.+ -HCl), 140(100%)                                                                    10                                         33      161-178  465(M.sup.+ -HCl), 140(100%)                                                                    10                                         34      181-188  542(M.sup.+ -2HCl), 92(100%)                                                                    10                                         35      182-190  498(M.sup.+ -2HCl), 134(100%)                                                                   10                                         36      110-116  497(M.sup.+ -Q36), 91(100%)                                                                     11                                         37      177-180  497(M.sup.+ -HCl), 91(100%)                                                                     10                                         38      110-122  541(M.sup.+ -Q36), 91(100%)                                                                     11                                         39      112-124  515(M.sup.+ -Q36), 109(100%)                                                                    11                                         40      184-187  515(M.sup.+ -HCl), 109(100%)                                                                    10                                         41      82-86    543(M.sup.+ -Q36), 234(100%)                                                                    11                                         42      88-91    557(M.sup.+ -Q35), 522(100%)                                                                    11                                         43      105-112  559(M.sup.+ -Q36), 109(100%)                                                                    11                                         44      174-178  559(M.sup.+ -HCl), 109(100%)                                                                    10                                         45      165-173  526(M.sup.+ -HCl), 92(100%)                                                                     10                                         46      162-168  449(M.sup.+ -HCl), 169(100%)                                                                    10                                         47      136-138  525(M.sup.+ -HCl), 91(100%)                                                                     10                                         48      130-133  569(M.sup.+ -HCl), 91(100%)                                                                     10                                         49      130-135  553(M.sup.+ -HCl), 91(100%)                                                                     10                                         50      134-135  515(M.sup.+ -44-Q35), 109(100%)                                                                 10                                         51      133-137                    10                                         52      128-129  529(M.sup.+ -Q35), 109(100%)                                                                    10                                         53      134-135  531(M.sup.+ -2Q35), 207(100%)                                                                   10                                         54      175-179  497(M.sup.+ -2Q35), 91(100%)                                                                    10                                         55      195-196  515(M.sup.+ -2Q35), 109(100%)                                                                   10                                         56      126-129  557(M.sup.+ -Q35), 109(100%)                                                                    10                                         57      142-144  543(M.sup.+ -2Q35), 109(100%)                                                                   10                                         58      121-125  564(M.sup.+ -2Q35), 109(100%)                                                                   10                                         59      108-110  548(M.sup.+ -2Q35), 143(100%)                                                                   10                                         60      126-128  646(M.sup.+ -2Q35), 109(100%)                                                                   10                                         61      113-117  548(M.sup.+ -Q35), 143(100%)                                                                    10                                         62       98-103  496(M.sup.+), 91(100%)                                                                           1                                         63      112-115  482(M.sup.+ -Q35), 91(100%)                                                                     10                                         64      166-171  558(M.sup.+ -Q35), 109(100%)                                                                    10                                         65      162-163  545(M.sup.+ -2Q35), 109(100%)                                                                   10                                         66      174-175  541(M.sup.+ -Q35), 91(100%)                                                                     10                                         67      104-107  592(M.sup.+ -Q36), 143(100%)                                                                    10                                         68      108-110  573(M.sup.+ -Q35), 109(100%)                                                                    10                                         69       98-100  601(M.sup.+ -Q35), 109(100%)                                                                    10                                         70      184-186  559(M.sup.+ -2Q35), 109(100%)                                                                   10                                         71      118-119  592(M.sup.+ -2Q35), 143(100%)                                                                   10                                         72      130-132  690(M.sup.+  + 1-2Q35), 109(100%)                                                               10                                         73      106-109  691(M.sup.+  + 1-Q35), 109(100%)                                                                10                                         74      80-83    540(M.sup.+)       6                                         75      105-108  526(M.sup.+ -Q35), 91(100%)                                                                     10                                         76      102-103  573(M.sup.+ -Q35), 109(100%)                                                                    10                                         77      94-96    615(M.sup.+  + 1-2Q35), 106(100%)                                                               10                                         78      87-89    465(M.sup.+ -106), 106(100%)                                                                     7                                         79      118-121  599(M.sup.+  + 1-Q35), 106(100%)                                                                10                                         80      121-123  613(M.sup.+  + 1-Q35), 106(100%)                                                                10                                         ______________________________________                                    

    ______________________________________                                        FORMULATION EXAMPLE 1 (Tablets)                                               ______________________________________                                        Compound No. 39          10     g                                             Lactose                  20     g                                             Starch                   4      g                                             Starch for paste         1      g                                             Magnesium stearate       0.1    g                                             Carboxymethyl cellulose calcium                                                                        7      g                                             Total                    42.1   g                                             ______________________________________                                    

The above components were mixed in a usual manner, and formulated intosugar-coated tablets each containing 50 mg of an active ingredient.

    ______________________________________                                        FORMULATION EXAMPLE 2 (Capsules)                                              ______________________________________                                        Compound No. 43           10    g                                             Lactose                   20    g                                             Microcrystal cellulose    10    g                                             Magnesium stearate        1     g                                             Total                     41    g                                             ______________________________________                                    

The above components were mixed in a usual manner, and filled intogelatin capsules to obtain capsules each containing 50 mg of an activeingredient.

    ______________________________________                                        FORMULATION EXAMPLE 3 (Soft capsules)                                         ______________________________________                                        Compound No. 7             10    g                                            Corn oil                   35    g                                            Total                      45    g                                            ______________________________________                                    

The above components were mixed and formulated in a usual manner toobtain soft capsules.

    ______________________________________                                        FORMULATION EXAMPLE 4 (Ointment)                                              ______________________________________                                        Compound No. 25           1.0    g                                            Olive oil                 20     g                                            White vaseline            79     g                                            Total                     100    g                                            ______________________________________                                    

The above components were mixed in a usual manner to obtain 1% ointment.

    ______________________________________                                        FORMULATION EXAMPLE 5 (Aerosol suspension)                                    ______________________________________                                        (A)   Compound No. 37           0.25%                                               Isopropyl myristate       0.10%                                               Ethanol                  26.40%                                         (B)   A 60-40% mixture of 1,2- 73.25%                                               dichlorotetrafluoroethane and                                                 1-chloropentafluoroethane                                               ______________________________________                                    

The above composition (A) was mixed. The solution mixture therebyobtained was charged in a container equipped with a valve, and thepropellant (B) was injected from the valve nozzle to a gauge pressure offrom about 2.46 to 2.81 mg/cm² to obtain an aerosol suspension.

TEST EXAMPLES

I. Bronchodilating effect

1. In vitro test

Drug:

A test sample drug was dissolved in 100% dimethylsulfoxide (DMSO, Wakojunyaku) and diluted for use. Leukotriene D₄ (LTD₄, Ultrafine) andisoproterenol (Isoproterenol, Sigma) were diluted with distilled water.Indomethacin (Indo, Sigma) was dissolved in 100% ethanol (EtOH, KomuneKagaku). Aminophylline (AP, Sigma), histamine dihydrochloride (His, WakoJunyaku) was dissolved in distilled water. The final concentrations ofDMSO and EtOH in a bath were made not higher than 0.25% v/v and nothigher than 0.1% v/v, respectively.

Method 1:1:

A guinea-pig of 300-450 g was exsanguinated, and the trachea was takenout. After removing fat and connective tissues, it was cut and dividedinto 2 to 3 spiral strips, each having a width of about 2 mm andcontaining 4 smooth muscle tissues. Each specimen thus prepared wassuspended in an organ bath of 8 ml containing a modified Tyrode solutionaerated with 95% O₂ +5% CO₂ at 37° C., and a load of 1 g was appliedthereto. The relaxation of the muscle was recorded by a pen recorder(Yokogawa Hokushin Electric, type 3066) by means of an isotonictransducer (Nihon Kohden, TD-112S).

The composition of the modified Tyrode solution was as follows (mM):

NaCl 137, KCl 2.7, CaCl₂ 1.8, MgCl₂ 1.0, NaHCO₃ 20, NaH₂ PO₄ 0.32,Glucose 11.

The specimen was allowed to stand for 50-60 minutes, and was contractedwith histamine dihydrochloride (100 μM). After the reaction becameconstant, it was washed and allowed to stand for 20-30 minutes.Indomethacin (5 μM) was added thereto, and after incubation for 30minutes, the specimen was contracted by adding LTD₄ (30 nM). After thereaction became stable, a test sample drug was accumulativelyadministered. Finally, AP (1 mM) was added to achieve the maximumrelaxation reaction. The result was expressed by relaxation percentrelative to the relaxation by AP which was rated 100%, and aconcentration to achieve 50% relaxation (EC₅₀, μM) was measured. As acontrol drug, AP was used. The results are shown in Table III-1.

                  TABLE III-1                                                     ______________________________________                                        Test Compound                                                                 No.             EC.sub.50 (μM)                                             ______________________________________                                         4              1.7                                                            5              0.42                                                           7              0.49                                                          13              0.45                                                          15              0.48                                                          17              3.3                                                           22              0.39                                                          23              1.3                                                           24              2.0                                                           25              0.47                                                          26              0.75                                                          27              4.0                                                           30              2.6                                                           31              6.9                                                           34              3.8                                                           35              6.6                                                           36              0.32                                                          39              0.16                                                          43              0.40                                                          47              0.77                                                          48              0.95                                                          49              1.1                                                           51              6.1                                                           53              3.1                                                           54              2.4                                                           55              7.3                                                           64              0.32                                                          66              0.18                                                          67              0.17                                                          76              0.69                                                          Aminophylline   178                                                           ______________________________________                                    

Method 1-2:

The same measuring method as method 1-1 was employed. The specimen wasallowed to stand for from 60 to 90 minutes and then relaxed by anaddition of 1 μM of isopreterenol. The specimen was washed, and thisoperation was repeated at an interval of from 30 to 40 minutes until aconstant relaxation reaction was reached. Then, a test sample drug wasaccumulately applied to relax the specimen. Finally, 1 mM of AP wasadded to achieve the maximum relaxation reaction. The result wasexpressed by relaxation percent relative to the relaxation by AP whichwas rated 100%, and a concentration to achieve 50% relaxation (EC₅₀, μM)was obtained. The final concentration of DMSO in the bath was adjustedto be 0.2 v/v %. As a control drug, AP was used. The results are shownin Table III-2.

                  TABLE III-2                                                     ______________________________________                                        Test Compound                                                                 No.             EC.sub.50 (μM)                                             ______________________________________                                        16              0.34                                                          24              0.98                                                          26              0.91                                                          36              0.24                                                          39              0.17                                                          43              0.28                                                          47              0.54                                                          48              0.21                                                          51              0.097                                                         54              0.3                                                           61              0.31                                                          62              0.05                                                          64              0.061                                                         65              0.36                                                          66              0.067                                                         67              0.041                                                         69              0.43                                                          71              0.25                                                          73              0.49                                                          74              0.046                                                         75              0.40                                                          76              0.048                                                         77              0.057                                                         78              0.014                                                         79              0.041                                                         80              0.039                                                         Aminophylline   37                                                            ______________________________________                                    

(2) in vivo test

Effect on anaphylactic bronchoconstriction mediated by endogeneouslyliberated SRS-A in passively sensitized guinea-pig

Male guinea-pigs (350-450 g) were passively sensitized with intravenous(i.v.) injection of 0.125 ml rabbit anti-EA (egg albumin) serum (CappleLaboratories) 1 to 2 days preceding the experiment. Antigen-inducedanaphylactic bronchoconstrictions mediated by endogeneously liberatedSRS-A were measured by modified method of Konzett and Rossler (Arch.Exp. Path. Pharmak., 195, 71, 1940). Sensitized quinea-pigs wereanaesthetized with intraperitoneal injection of urethane (1.5 g/kg). Theright jugular vein was cannulated for the administration of the allagents and trachea was cannulated to record total pulmonary resistance.Guinea-pigs were artificially ventilated by a small animal respirator(Shinano, Model SN-480-7) set at a stroke volume of 4.5 ml and a rate of50 breaths per min. The change in pulmonary resistance was measured witha pressure transducer (Nihon Kohden, Model TP-602T) connected to aT-tube on the tracheal cannula. The percentage of the maximumbronchoconstriction obtained by clamping off the trachea. Followingsurgical preparation, the animals were pretreated with indomethacin (2mg/kg, 10 min), pyrilamine (2 mg/kg, 6 min) and propranolol (0.1 mg/kg,5 min) prior to the EA challenge (0.2 mg/kg). All test compounds wereadministered orally 2 hours before the EA challenge. Inhibition (%) ofbronchoconstriction was determined as follows: Inhibition (%)=(1.0-%maximum bronchoconstriction in test/% maximum bronchoconstriction incontrol)×100. The maximum bronchoconstriction was 62±6% (Mean±S.E.M;n=6) and the number of test animals was 5-6.

The inhibition ratio at a dose of 30 mg/kg of the test compound is shownin Table III-3.

                  TABLE III-3                                                     ______________________________________                                        Test Compound   Inhibition                                                    No.             (%)                                                           ______________________________________                                         7              59                                                             8              32                                                            25              59                                                            26              36                                                            36              41                                                            37              54                                                            39              63                                                            43              62                                                            47              37                                                            64              26                                                            67              29                                                            74              30                                                            77              65                                                            78              54                                                            80              30                                                            ______________________________________                                    

II. Antiallergic effect

Binding test employing ³ H-pyrilamine (histamine H₁ receptor-bindingtest)

The test was carried out in accordance with the method of Chang et al(j. Neurochem., 32, 1653 (1979)).

Tritiated pyrilamine was added to a suspension of bovine cerebellum anda 50 mM phosphate buffer solution (pH 7.5), and the mixture was left tostand still at 25° C. for 30 minutes. Then, the mixture was rapidlyfiltered under suction through a glass fiber filter paper, and the radioactivities on the filter paper were measured. The inhibition ratioagainst H₁ -receptor at a concentration of the test compound being 10μM, was calculated by the following equation.

    Inhibition ratio (%)={1-(binding amount in the presence of the drug-non-specific binding amount)/(total binding amount-non-specific binding amount)}×100

where the total binding amount is ³ H-pyrilamine-binding radio activityin the absence of the test compound, and the non-specific binding amountis ³ H-pyrilamine-binding radio activity in the presence of 10 μM oftriprolisine. The results are shown in Table IV.

                  TABLE IV                                                        ______________________________________                                        Test Compound   Inhibition                                                    No.             (%)                                                           ______________________________________                                         7              56.1                                                           8              56.5                                                          17              55.8                                                          22              86.6                                                          23              92.2                                                          24              89.2                                                          25              94.4                                                          26              92.6                                                          29              93.6                                                          30              90.5                                                          ______________________________________                                    

III. Anti-platelet aggregation effect Anti-platelet aggregation effectin rabbits

Blood was collected from the abdominal artery of Japanese white malerabbits (weight: 1.8 to 2.5 kg) into a syringe containing 1/10 volume3.8% sodium citrate. The blood thus obtained was subjected to acentrifugation at 200×g for 7 minutes at room temperature to obtainplatelet rich plasma (PRP). Furthermore, the residue was subjected to acentrifugation at 2000×g for 10 minutes to obtain platelet poor plasma(PPP). The measurement was effected by diluting PRP with PPP to300,000/mm³. PRP and PPP were placed in a cuvette, and the measurementrange of transmittance was adjusted to 0% in the case of PRP and to 100%in the case of PPP. Thereafter, a test sample drug dissolved in 100%dimethylsulfoxide (DMSO) was added to PRP (the final concentration ofDMSO: 0.25%). After incubation was effected at 37° C. at 900 rpm for 2minutes, an aggregating agent was added to record an aggregation curve.The anti-platelet aggregation effect of the test sample drug wasexpressed by a concentration (IC₅₀ : μM) at which the aggregation ofcontrol sample was 50% inhibited. The aggregating agent ADP was used atthe minimum concentration (5 to 10 μM) which caused the maximumaggregation. The measurement of platelet aggregation was carried out byusing NBS HEMA TRACER 601. The results are shown in Table V.

                  TABLE V                                                         ______________________________________                                        Test Compound                                                                 No.             IC.sub.50 (μM)                                             ______________________________________                                         4              5.2                                                            5              4.1                                                            6              3.9                                                            7              5.4                                                            8              5.5                                                           13              2.9                                                           14              3.5                                                           15              4.5                                                           16              5.2                                                           22              2.1                                                           23              4.6                                                           25              5.1                                                           36              1.6                                                           38              1.2                                                           39              1.4                                                           43              2.2                                                           47              5.7                                                           48              4.0                                                           51              1.1                                                           64               0.39                                                         67              0.4                                                           ______________________________________                                    

INDUSTRIAL APPLICABILITY

As is evident from the above results, the compounds of the presentinvention have excellent bronchodilating activities, antiallergicactivities and antiplatelet aggregation activities. The compounds of thepresent invention exhibit strong pharmacological activities even by oraladministration. Thus, they can be prophylactic and therapeutic drugsuseful for immediate allergic diseases such as bronchial asthma,allergic rhinitis, hives and hey fever, various inflammatory diseasessuch as rhematic arthritis and spinal anthritis, ischemic diseases suchas angina pectoris and cardiac infarction, and various thromboticdiseases.

We claim:
 1. A 3(2H)-pyridazinone compound of the formula (I): ##STR66##wherein each of R¹, R² and R³ which are independent of one another, is ahydrogen atom or a C₁₋₄ alkyl group, X is a chlorine atom or a bromineatom, Y¹ is a hydrogen atom, a halogen atom, a nitro group, an aminogroup or a C₁₋₄ alkoxy group, Y² is a hydrogen atom, a halogen atom, ahydroxyl group, a C₁₋₄ alkyl group or a C₁₋₄ alkoxy group, A is a C₁₋₅alkylene chain which may be substituted by a hydroxyl group, B is acarbonyl group or a methylene chain which may be substituted by a C₁₋₄alkyl group, R⁴ and R⁵ form together with the adjacent nitrogen atom a4-substituted piperazine ring of the formula: ##STR67## {wherein R⁶ is aC₁₋₄ alkyl group (this alkyl group may be substituted by one or moresubstituents selected from a group of substituents consisting of (i) aC₁₋₄ alkyl group, (ii) a phenyl group which may be substituted by Y³(wherein Y³ is a hydrogen atom, a halogen atom, a C₁₋₄ alkyl group, aC₁₋₄ alkoxy group, an amino group, an N-formyl group or a C₁₋₄alkylcarbonylamino group), (iii) ##STR68## (wherein each of R⁷ and R⁸ isa hydrogen atom, or R⁷ and R⁸ form together with the carbon atoms towhich they are bonded, a benzene ring, and each of A, B, C and D whichare independent of one another, is a nitrogen atom or a carbon atom) and(iv) ##STR69## (wherein Y³ is as defined above, and R⁹ is a C₁₋₄ alkylgroup or a benzyl group which may be substituted by a C₁₋₄ alkyl group,a C₁₋₄ alkoxy group or a halogen atom)) or R⁶ is --COR¹⁰ (wherein R¹⁰ isa hydrogen atom or a C₁₋₄ alkyl group)}; or a pharmaceuticallyacceptable salt thereof.
 2. The 3(2H)-pyridazinone compound according toclaim 1, wherein each of R² and R³ is a hydrogen atom, and Y¹ is ahydrogen atom, a halogen atom, a nitro group or a C₁₋₄ alkoxy group; ora pharmaceutically acceptable salt thereof.
 3. The 3(2H)-pyridazinonecompound according to claim 2, wherein R⁴ and R⁵ form together with theadjacent nitrogen atom a 4-substituted piperazine ring of the formula:##STR70## wherein R¹² is (a) a C₁₋₄ alkyl group {this alkyl group may besubstituted by one or more substituents selected from a group ofsubstituents consisting of (i) C₁₋₄ alkyl group, (ii) a phenyl groupwhich may be substituted by Y³ (wherein Y³ is a hydrogen atom, a halogenatom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, an amino group, anN-formyl group or a C₁₋₄ alkylcarbonylamino group), (iii) ##STR71##(wherein each of R⁷ and R⁸ is a hydrogen atom, or R⁷ and R⁸ formtogether with the carbon atoms to which they are bonded, a benzene ring,and each of A, B, C and D which are independent of one another, is anitrogen atom or a carbon atom) and (iv) ##STR72## (wherein Y³ isdefined as above, and R⁹ is a C₁₋₄ alkyl group or a benzyl group whichmay be substituted by a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group or ahalogen atom)} or (b) --COR¹⁰ ; (wherein R¹⁰ is a hydrogen atom or aC₁₋₄ alkyl group), or a pharmaceutical acceptable salt thereof.
 4. The3(2H)-pyridazinone compound according to claim 3, wherein R⁴ and R⁵ formtogether with the adjacent nitrogen atom a 4-substituted piperazine ringof the formula: ##STR73## wherein R¹³ is (a) methyl group {this methylgroup may be substituted by one or more substituents selected from agroup of substituents consisting of (i) a phenyl group which may besubstituted by Y³ (wherein Y³ is a hydrogen atom, a halogen atom, a C₁₋₄alkyl group, a C₁₋₄ alkoxy group, an amino group, an N-formyl group or aC₁₋₄ alkylcarbonylamino group), (ii) ##STR74## (wherein each of R⁷ andR⁸ is a hydrogen atom, or R⁷ and R⁸ form together with the carbon atomsto which they are bonded, a benzene ring, and each of A, B, C and Dwhich are independent of one another, is a nitrogen atom or a carbonatom) and (iii) ##STR75## (wherein Y³ is as defined above, and R⁹ is aC₁₋₄ alkyl group or a benzyl group which may be substituted by a C₁₋₄alkyl group, a C₁₋₄ alkoxy group or a halogen atom)} or (b) --COR¹⁰(wherein R¹⁰ is a hydrogen atom or a C₁₋₄ alkyl group); or apharmaceutically acceptable salt thereof.
 5. The 3(2H)-pyridazinonecompound according to claim 4, wherein Y² is a a halogen atom or a C₁₋₄alkoxy group; or a pharmaceutically acceptable salt thereof.
 6. The3(2H)-pyridazinone compound according to claim 5, wherein R⁴ and R⁵ formtogether with the adjacent nitrogen atom a 4-substituted piperazine ringof the formula: ##STR76## wherein R¹⁴ is (a) ##STR77## (wherein Y⁴ is ahydrogen atom, a halogen atom, an amino group, an N-formyl group or aC₁₋₄ alkylcarbonylamino group), ##STR78## (wherein R¹⁵ is a benzyl groupwhich may be substituted by a halogen atom); or a pharmaceuticallyacceptable salt thereof.
 7. The 3(2H)-pyridazinone compound or thepharmaceutically acceptable salt thereof according to claim 1, which is4-chloro-5-3-{4-(benzyl)-piperazin-1-yl}-carbonylmethoxy-4-methoxybenzylamino!-3(2H)-pyridazinone.8. The 3(2H)-pyridazinone compound or the pharmaceutically acceptablesalt thereof according to claim 1, which is 4-chloro-5-3-{4-(4-fluorobenzyl)-piperazin-1-yl}-carbonylmethoxy-4-methoxybenzylamino!-3(2H)-pyridazinone.9. The 3(2H)-pyridazinone compound or the pharmaceutically acceptablesalt thereof according to claim 1, which is 4-chloro-5-3-{4-(4-chlorobenzyl)-piperazin-1-yl}-carbonylmethoxy-4-methoxybenzylamino!-3(2H)-pyridazinone.10. The 3(2H)-pyridazinone compound or the pharmaceutically acceptablesalt thereof according to claim 1, which is 4-chloro-5-3-{4-(4-aminobenzyl)-piperazin-1-yl}-carbonylmethoxy-4-methoxybenzylamino!-3(2H)-pyridazinone.11. The 3(2H)-pyridazinone compound or the pharmaceutically acceptablesalt thereof according to claim 1, which is 4-chloro-5-3-{4-(4-N-acetylaminobenzyl)-piperazin-1-yl}-carbonylmethoxy-4-methoxybenzylamino!-3(2H)-pyridazinone.12. A process for producing the 3(2H)-pyridazinone compound or itspharmaceutically acceptable salt as defined in claim 1, which comprisesreacting a 4,5-dihalo-3(2H)-pyridazinone compound of the formula (II):##STR79## wherein R¹ is a hydrogen atom or a C₁₋₄ alkyl group, X is achlorine atom or a bromine atom, and Y¹ is a hydrogen atom, a halogenatom, a nitro group, an amino group or a C₁₋₄ alkoxy group, and analkoxybenzylamine derivative of the formula (III) or its salt: ##STR80##wherein each of R² and R³ which are independent of each other, is ahydrogen atom or a C₁₋₄ alkyl group, Y² is a hydrogen atom, a halogenatom, a hydroxyl group, a C₁₋₄ alkyl group or a C₁₋₄ alkoxy group, A isa C₁₋₅ alkylene chain which may be substituted by a hydroxyl group, B isa carbonyl group or a methylene chain which may be substituted by a C₁₋₄alkyl group, together with the adjacent nitrogen atom a 4-substitutedpiperazine ring of the formula: ##STR81## {wherein R⁶ is a C₁₋₄ alkylgroup (this alkyl group may be substituted by one or more substituentsselected from a group of substituents consisting of(i) a C₁₋₄ alkylgroup, (ii) a phenyl group which may be substituted by Y³ (wherein Y³ isa hydrogen atom, a halogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkoxygroup, an amino group, an N-formyl group or a C₁₋₄ alkylcarbonylaminogroup), (iii) ##STR82## (wherein each of R⁷ and R⁸ is a hydrogen atom,or R⁷ and R⁸ form together with the carbon atoms to which they arebonded, a benzene ring, and each of A, B, C and D which are independentof one another, is a nitrogen atom or a carbon atom) and (iv) ##STR83##wherein Y³ is as defined above, and R⁹ is a C₁₋₄ alkyl group or a benzylgroup which may be substituted by a C₁₋₄ alkyl group, a C₁₋₄ alkoxygroup or a halogen atom)) or R⁶ is --COR¹⁰ (wherein R¹⁰ is a hydrogenatom or a C₁₋₄ alkyl group)} optionally in the presence of anacid-binding agent.
 13. A composition comprising a pharmaceuticallyacceptable carrier and, in bronchodilator, antiallergic or antiplatelet,effective amounts, the 3(2H)-pyridazinone compound or itspharmaceutically acceptable salt as defined in claim
 1. 14. A method fortreating a patient in need thereof with a bronchodilator comprisingadministering the 3(2H)-pyridazinone compound or its pharmaceuticallyacceptable salt as defined in claim 1 in an effective amount.
 15. Amethod for treating a patient in need thereof with a antiallergic drugcomprising administering the 3(2H)-pyridazinone compound or itspharmaceutically acceptable salt as defined in claim 1 in an effectiveamount.
 16. A method for treating a patient in need thereof with aantiplatelet agent comprising administering the 3(2H)-pyridazinonecompound or its pharmaceutically acceptable salt as defined in claim 1in an effective amount.